\r\n\tThis book aims to present some of the most exciting developments in the subject of NMR spectrosocpy.
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1. Introduction
The high success rates for the dental rehabilitation of patients with endosseous implants have resulted from many research approaches with the aim of enhancing and accelerating bone anchorage to the implant, thereby providing optimal support for the intraoral prosthetic devices. This revolutionary breakthrough has first evolved from the research efforts of the Brånemark group in the late 1960s by pioneering the insertion of machined screw-type commercially pure titanium (cpTi) implants with minimum surgical trauma and a consolidation period for the healing of the bone (Albrektsson et al., 1981; Brånemark et al., 1969). This first endosseous titanium implant was produced with an industrial turning process, which led to surfaces with minimally rough topographies at the micron level. The bone bonding ability, termed as “osseointegration” by Brånemark et al. (1977), of this machined implant was mainly the result of the proper surgical technique providing macro-stability to the implant and the biocompatible nature of the bulk titanium. In the past three decades, much has been learned about the concept of osseointegration and significant improvements on the design and surface of implants were done to eliminate the important challenges of the implant dentistry.
Osseointegration was first defined as a direct contact between living bone and the surface of a load-carrying implant at the histological level (Brånemark, 1983) and, in clinical terms, as a biomechanical phenomenon whereby clinically asymptomatic rigid fixation of the implant is achieved and maintained in bone during functional loading (Albrektsson & Johansson, 2001). Typically, an implant is considered to be osseointegrated when there is an absence of movement between the implant and bone under normal conditions of loading following a defined healing period. This clinical state is the result of direct bone apposition to an implant surface without formation of a poorly vascularised collagenous capsule, termed as fibrous encapsulation. Although the concept of “osseointegration” was first put forth to define the connection between bone and titanium, it has been shown that bone anchorage can also be achieved with the use of other materials without an adverse tissue reaction (Wenz et al., 2008). Thus, osseointegration is currently accepted as a general term for bone-implant surface contact. However, the quality of the host bone/foreign implant interface is mostly affected by the characteristics of the material. Especially, titanium has been shown to have a closer contact with the calcified tissue and to be covered by a thinner proteoglycan structure compared to zirconium and stainless steel (Albrektsson et al., 1985, 1986). Various studies have also suggested that titanium exhibits a better biocompatible nature and less foreign body reaction compared to other conventional materials (Eisenbarth et al., 2004; Hallab et al., 2003). It has been stated that osseointegration of titanium does not result due to a positive tissue reaction, instead it occurs in the absence of a negative tissue response (Stanford & Keller, 1991). Therefore, the bioinert character of titanium is the main reason of its enhanced bone bonding behaviour. Now, osseointegration of titanium is widely accepted as the prerequisite for dental implant success in dentistry. Although the reported success rates are higher than 90% in controlled clinical trials (Henry et al., 1996; Jemt et al., 1996), important challenges, such as the long latency period between implant placement and loading, remain to be elucidated. Also, achieving high success rates in specific patient groups (e.g. diabetics, oncology patients, smokers) seems to be elusive (Esposito et al., 1998). Over the past two decades, elevating the local quality and quantity of the host tissue for an optimal osseointegration was the major goal of implant dentistry in order to overcome these drawbacks. Therefore, various approaches have focused on finding alternative methods to accelerate and optimize osseointegration, aiming at sufficient mechanical integrity to withstand occlusal forces at an early period (Morton et al., 2010).
During the first 10–20 years of understanding the healing mechanisms of traumatized bone where implants are placed, the concept that successful osseointegration was the result of titanium implant biocompatibility dominated clinical thinking. Subsequently, implant surface modifications encouraged new considerations of improvements in bone formation at the implant surface. Since the biological mechanisms at the bone-implant interface determine the fate of the implant, characteristics of the implant surface play a central role in challenging the process of osseintegration with early loading. Upon insertion, premature loading can disrupt the healing process and may result in early failure of the implant. Enhancing the biological response using a surface science approach therefore has attracted the attention of many research groups (Ramazanoglu et al., 2011; von Wilmowsky et al. 2009). It is well established that characteristics of the implants surface, such as nano- and micro-topography, and physicochemical composition, have a major influence on the outcome of osseointegration, especially at the histological level, aiming at biological and morphological compatibilities (Mendonça et al., 2008).
In general, the implantation of devices for the maintenance or restoration of a body function imposes extraordinary requirements on the materials of construction. Foremost among these is an issue of biocompatibility. It was found, after extensive literature review, that there are three major required compatibilities for placed implants to exhibit biointegration to receiving hard tissue and biofunctionality thereafter. They include biological comatobility (in short, called as biocompatibility), mechanical compatibility, and morphological compatibility to receiving host tissues (Oshida et al., 1994; Oshida, 2000; Oshida et al., 2010). Accordingly, numerous studies have been conducted to meet aforementioned requirements for successful implant systems (i.e., mechanical compatibility, biological compatibility, and morphological compatibility) by altering surface characteristics for overcoming the potential drawbacks of the implant therapy ( Oshida, 2007; Oshida et al., 2009). This chapter focuses on essential mechanisms governing the peri-implant healing and surface science approaches for enhancing osseointegration. The future of the implant surface science and prospective tissue engineering attempts for the biological constitution of the peri-implant area are also topics of this chapter for providing ideas for forthcoming studies.
2. Healing around the endosseous implant
Ossification mechanisms that occur following the placement of the implant are very important for understanding the biologic response to endosseous implants. Osborn (1979) categorized this bio-response into the following three groups: (1) biotolerant type, characterized by distance osteogenesis, the implant is not rejected from the tissue, but it is surrounded by a fibrous connective tissue, (2) bioinert type, characterized by contact osteogenesis, the osteogenic cells migrate directly to the surface where they will establish de novo bone formation, and (3) bioreactive type, the implant allows new bone formation around itself, thereby exchanging ions to create a chemical bond with the bone. Upon insertion, various implant materials exhibit different biologic responses. While biotolerant materials, such as gold, cobalt-chromium alloys, stainless steel, polyethylene and polymethylmethacrylate, exhibit distance osteogenesis, titanium and titanium alloys are accepted to be bioinert according to their surface oxides (Kienapfel et al., 1999). Besides, the rutile-type oxide, which is formed on titanium as a titanium dioxide, is described as a stable crystalline form similar to ceramics in its bioreactive behaviour (Zhao et al., 2005). Although titanium has superior characteristics compared to other implant metals, the ostoconductivity of titanium is lower than calcium phosphate (CaP) based bioceramics (Kilpadi et al., 2001). Therefore, CaP based ceramics are referred to be bone-bonding materials, whereas titanium is a nonbonding material to bone (Hench & Wilson, 1984). Therefore, approaches have mainly focused on enhancing the bioactivity of titanium and providing a higher osteoconductivity to the bulk material by altering the surface properties.
The character of the host tissue also plays an important role on the ossification mechanism following implantation. Understanding the different peri-implant healing cascades of the cortical and trabecular bone is crucial for better orientating the osseointegration in poor quality bone (Davies, 1996). Following surgical trauma, the vascular injury of the cortex results in death of the peri-implant cortical bone, and followed by a slow proceeding osteoclastic remodelling. The removal of the injured tissue by osteoclasts and the subsequent formation of the new bone is a long lasting process. Therefore, the healing around the implant in cortical bone results in distance osteogenesis. Although this slow remodelling phase provides early stability in cortical bone leading to low rate of implant failure (Adell et al., 1981), especially in the parasymphyseal mandible, it is a handicap for the surface science approaches for enhancing the osseointegration histologically. On the other hand, the trabecular bone enables the migration of osteogenic cells due to its marrow component. The colonization of differentiating progenitor cells on the implant surface and de novo bone formation provides the evidence that peri-implant healing in trabecular bone occurs via contact osteogenesis. Actually, the presence of osteprogenitor populations in the spongious bone, which is characterized to be of poor quality in implant dentistry (Lekholm and Zarb type III and IV bone), favours the migration and bone forming activity of these cells directly on the surface when the implant is considered to be bioinert (Marco et al., 2005). In the recent decades, the development of novel osteoconductive titanium surfaces, that increased the local quantity and quality of osseous tissue at the interface, thereby improved the success of implants, especially in regions of the jaw such as the edentulous posterior maxillae where the cortical thickness is frequently insufficient for the primary stability.
The surgical placement of the implant results in injury of the host bone. If the implant is considered to be bioinert, the body responds to this injury with physiological mechanisms similar to the bone fracture healing. Following implant placement, the implant surface first gets in contact with the blood originating from the injured vessels facing the implant cavity. After several seconds, the surface is completely covered with a thin layer of serum proteins. This protein modification of the surface occurs for all implant materials in the same way. However, the type and surface characteristics of the material have a major influence on the structure and conformation of this protein layer (Dee et al., 2002). Shortly after protein adsorption, the surface becomes associated with thrombocytes. As a result of thrombocyte aggregation and degranulation on the surface, coagulation mechanisms take place and cytokines (e.g. transforming growth factor- (TGF-) and platelet derived growth factor (PDGF)) and several vasoactive factors (e.g. serotonin and histamine) are released from cytoplasmic granules of thrombocytes. These chemoattractants stimulate proliferation and migration of various cells, thereby orientating the peri-implant healing mechanisms (Dereka et al., 2006). For example, PDGF has important mitogenic and migrative effects on several cell types, such as inflammatory leukocytes, osteoblasts, smooth muscle cells and fibroblasts (Heldin & Westermark, 1999).
Polymorphonuclear neurophils (PMNs) are also first group of cells that play an important role in the inflammatory response. PMNs dominate the bone-implant interface at the first and second days. The number of PMNs tends to decrease when bacteria and endotoxins are not present at the interface. At the second day of healing, monocyte migration and macrophage accumulation starts to take place (Davies, 2003). PMNs and macrophages remove dead cells, extracellular matrix (ECM) residues and bacteria. Beside their role on the initial inflammatory phase, another mission of macrophages is the expression of cytokines, such as fibroblast growth factor (FGF), PDGF and vascular endothelial growth factor (VEGF). Thus, they provide important signals in order to stimulate the recruitment of osteogenic and endothelial progenitors for the next proliferative phase. The release of vasoactive amines, thrombocyte and leukocyte infiltration, the establishment of the coagulum and fibrin network, macrophage actions are important events that occur at the inflammatory phase. This first phase, which can sometimes extend to five days, is followed by the removal of the coagulum by PMNs and subsequently by monocytes, at the same time angiogenesis starts also to take place (Stanford & Keller, 1991). The growth of new capillaries into the fibrin network is mostly stimulated by the growth factors (primarily FGF and VEGF) expressed by macrophages and endothelial cells as a response to hypoxic and acidic nature of the bone-implant interface (Schliephake, 2002). In this way, the proliferation, maturation and organization of endothelial cells to new capillary tubes take place, thereby providing oxygen and nutrients to the newly formed tissue at the interface.
The behaviour of blood cells inside the fibrin-based structural matrix has a major impact on the healing mechanisms at the bone-implant interface. Besides, the quality of bone healing around an implant is also affected by the capacity of osteogenic cells to proliferate and migrate. Meyer et al. (2004) have demonstrated that the osteoprogenitor cells started to attach the implant surface after one day following insertion. This was a similar finding, as stated by Davies (1996), showing that early recruitment and colonization of mesenchymal stem (MSCs) cells occur on an implant surface in a short time through modulation of white blood cells, fibrin network and thrombocytes (Park & Davies, 2000). The three dimensional structure of fibrin matrix and the migrating effects of growth factors expressed by the first arriving cells play an important role in the establishment of an osteoprogenitor reservoir at the interface. Therefore, the chemistry of the implant material and its surface characteristics are of special interest in implantology, since they initially influence the binding capacity of fibrin and the release of growth factors, thereby affecting the migration of mesenchymal cells directly (Puleo & Nanci, 1999).
Titanium implant materials possess ideal fibrin retention on their surface. Through this fibrin matrix, osteogenic cells having the migration ability arrive the implant surface and start to produce bone directly on the surface. Davies (2003) termed this phenomenon as de novo bone formation through contact osteogenesis. Upon arrival to the surface, the differentiated osteogenic cells secrete the collagen-free matrix (cement lines / lamina limitans) for the mineralisation through calcium and phosphate precipitation. This layer, where the initial mineralisation occurs, consists of non-collagenous proteins (mostly osteopontin and bone sialoprotein) and proteoglycans (Klinger et al., 1998). Following calcium phosphate precipitation, the formation and mineralisation of collagen fibers take place. Thus, a non-collagenous tissue is established between the implant surface and the calcified collagen compartment through contact osteogenesis. This intermediary tissue is very important for the understanding the bonding mechanism between bone and a bioinert titanium implant.
Following the establishment of the calcified matrix on the implant surface, woven bone formation and organization of the bone trabeculae start to take place for the reconstitution of the damaged bone at the peri-implant area (Marco et al., 2005). Since the woven bone mostly consists of irregular shaped and loosely packed collagen fibers, it does not provide sufficient mechanical stability compared to the organized the lamellar bone. However, most of woven bone usually remodels in three months and replaced by the lamellar bone. At three months of healing the implant is mostly surrounded by a mixture of woven and lamellar bone (Chappard et al., 1999). The formation and remodeling of the new lamellar bone around the implant occur more rapidly in the regions where there is denser marrow component present. Therefore, the biologic fixation of the implant is achieved faster in the trabecular bone, while a better primary stability is obtained in the cortical bone following implantation.
An implant surface is considered to be clean following fabrication processes. If not stored under special conditions, contaminations (e.g. hydrocarbon, sulphur dioxide and nitric oxide) occur from the atmosphere (Kasemo & Lausmaa, 1988). In order to decrease and eliminate such risk of contamination, commercial implant surfaces are usually subjected to passivation treatments and stored carefully in optimal packages until usage. If such an implant is placed into the bone, its surface first get in contact with the blood, which is mostly composed of water molecules. Differently from the liquid water, the water molecules bind to the surface and form water mono- or bi-layer (Kasemo & Gold, 1999). The organization of water molecules differs according to the wettability characteristics of the surface (Lim & Oshida, 2001). While on hydrophilic surfaces the interaction with water molecules results in the dissociation of molecules and in the formation hydroxyl groups, the water binding capacity of hydrophobic surfaces is very low. Following the establishment of water overlayer, the ions (e.g. Cl- and Na+) enter the layer and become hydrated. The characteristics of an implant surface have a major implant on this arrangement of ions and their water shells. After the establishment of an intermediate layer composed of ions and water molecules, the biomolecules arrive at the surface in milliseconds. Proteins absorb first onto the surface, then change their conformation, denaturize and desorb from surface leaving their place to other proteins that have more affinity to the surface. Thus, a biologic layer having a different arrangement and conformation surrounds the surface.
It is well known that surface characteristics have an important effect on the adsorption of biomolecules by changing the arrangement of water molecules and ions (Puleo & Nanci, 1999). While on hydrophobic surfaces proteins bind with their hydrophobic regions, on hydrophilic surfaces the connection is established with the help of hydrophilic regions Kasemo & Gold, 1999). This protein overlayer is never considered to be static. It is subjected to structural and conformational changes in time. Normally the protein, which is found in higher concentration in the biological fluid, reaches and adsorbs to the surface first. Usually, this protein is afterwards replaced with another one that has a more affinity to the surface, although its concentration is low in the biological fluid. As a result of these adsorption and desorption mechanisms, a diverse layer which is composed of different protein is formed and maintained at the surface. The major role of this protein layer is the attachment of functionary cells of the healing process. If a bone implant is planning to be developed, the establishment of a surface, that generates an optimal protein composition and conformation for the attachment of osteogenic cells on itself, is one most important strategies of the production.
Several proteins (e.g. fibronectin, vitronectin, laminin, serum albumin and collagen) facilitate the attachment of osteogenic cells on titanium surfaces (Park et al., 2005; Yang et al., 2003). Therefore, the protein binding capacity of an implant surface is considered to be an important factor for as successful osseointegration, since surface properties, such as micro- and nano-topography (Lee et al. 2010), physicochemical composition (Park et al., 2005) and surface free energy (MacDonald et al., 2004), have an influence on the extend of protein adsorption. It has been documented that osteogenic cells preferably attach to the specific protein sequences, such as the arginine-glycine-aspartic acid (RGD) motif. This motif is found in various ECM proteins, including fibronectin, vitronectin, laminin and osteopontin (Ruoslahti, 1996). Osteogenic cells attach to these binding motifs using their membrane receptors, termed as integrins. Integrin mediated cell attachment is crucial for physiological and pathological mechanisms, such as the embryonic development, maintanance of tissue integrity, circulation, migration and phagocytic activity of leukocytes, wound healing and angiogenesis. Integrins are obligate heterodimers composed of two distinct glycoprotein subunits; and subunits (Hynes, 2002). Integrin subunits cross the plasma membrane with a long extracellular ligand, while generally a very short domain remains in the cytoplasm. For the integrin family eighteen and eight subunits have been characterized in mammals until now. Through the combination of these different and subunits, 24 distinct integrins can be assembled. A cell can modulate more than one integrin receptor and change their location, thereby modifying its capacity to bind to different protein sequences (Dee et al., 2002).
As mentioned before, adhesion-promoting proteins in blood (e.g. fibronectin, vitronectin and various collagen types) bind to integrins through an RGD-dependent pathway (Ruoslahti, 1996). But, there are also different domains within these proteins that have the ability to bind to integrins and provoke integrin-mediated cellular signalling cascades. Briefly, integrin-mediated cell attachment to ECM initiate several intracellular events, including protein kinase C and Na+/H+ antiporter, phophoinositide hydrolysis, tyrosine phosphorylation of membrane and intracellular proteins (Plopper et al., 1995). These mechanisms result in mitogen stimulated protein kinase activation by altering the cellular pH and calcium concentration. Thus, intracellular communication is established and the extracellular signal is transmitted to the nucleus. The cell responds to this integrin-mediated signal through migration, proliferation and differentiation (Sawyer et al., 2005). The response of osteogenic cells to the initial protein layer on the implant surface is very important for the activation of osteoblastic pathways through integrin-mediated signalling, thereby for optimal osseointegration. Therefore, the development of an implant surface, that favours an osteogenic protein conformation on itself, has been one of the major areas of implant surface science. In the recent decades, various approaches have focused on understanding the effect of the surface characteristics on the protein dependent mechanisms of cell adhesion, proliferation, differentiation and bone matrix deposition, aiming at the development of novel implant surfaces.
3. Surface treatments for enhanced osseointegration
The surface of a titanium implant plays a crucial role in determining the biological response of the host bone for several reasons (Fig.1.). The surface of titanium is the only region in contact with the bone, and is always different in characteristics from the bulk. Therefore, mainly the characteristics of the surface govern the healing mechanisms at the bone-implant interface. For enhancing the biomechanical anchorage of the implant and for promoting osseointegration at the histological level, the modification of surface topography or the coating of titanium with bioactive materials has captured the interest of many scientists, clinicians, and manufacturers as well (Oshida, 2007). Commonly used techniques to alter surface properties of titanium are as follows: sand-blasting (Rosa &Beloti, 2003), acid-etching (Juodzbalys et al., 2007), alkali-etching (Kim et al., 2000), plasma spraying (Vercaigne et al., 1998), electropolishing (Harris et al., 2007), anodic oxidation (Yamagami et al., 2005), hydroxylapatite (HA) (Dalton & Cook, 1995) and calcium phosphate (CaP) (Liu et al. 2004) coatings, etc. Such modifications have, in general, resulted in several changes in surface properties, including morphology, physicochemical composition and surface energy. Although various studies have shown that surface alterations, such as the resulting roughness, have improved the outcome of osseointegration (Abrahamsson et al., 2001; Buser et al., 1991), it is still poorly understood that either this enhancement was caused due to topographical reasons or fabrication-related changes in surface composition and wettability characteristics. Furthermore, the majority of published papers lack of an adequate surface characterization, as stated in the literature (Wennerberg & Albrektsson, 2009), that makes the evaluation of the effect of unique surface properties on osseointegration. However, general observations using different in vitro and in vivo studies can be still made to evaluate the effect of surface properties per se (topography, composition, crystal structure and wettability) on osseointegration. Commonly, two categories of surface properties are suggested to be the most important aspects for affecting the tissue response to the implant: surface topography and chemical composition. Therefore, this chapter focuses mainly on these two categories.
3.1. Topographical features of titanium surfaces
Any dental implant, once inserted into the host bone, first comes into contact with tissue fluids. The adsorption of biomolecules and the subsequent interactions of cells on an implant surface determine the fate of the implant. For many years, the “machined” surface of the Brånemark implant was the gold standard for implant surfaces. However, the decreased success rates of these smooth textured implants at compromised sites (Jaffin & Berman, 1991), especially at the posterior maxillae, motivated the approaches for finding better implant surfaces promoting bone formation. In the search for methods modifying
Figure 1.
Effect of submacron surface characteristics of the implant on the osteogenic response
surface properties to achieve better osseointegration, much attention has been focused on increasing the surface roughness for improving the interfacial retaining mechanics. The main idea behind the establishment of such a rough topography was to increase the surface area of the implant adjacent to the bone and to improve the cell adhesion to the surface, thereby achieving higher bone-to-implant contact and better biomechanical integrity (Oshida et al., 1994; Cooper, 2000). Until now, extensive number of papers has been published on this topic. Numerous studies have shown that moderate roughness and complex microtopographies are important for the likely development of bone-implant interfaces and for the enhanced osseointegration of titanium implants (Abrahamsson et al., 2001; Buser et al., 1991). Compared with smooth surfaces, implants with rough surfaces exhibited greater contact with bone (Al-Nawas et al., 2008). However, systematic reviews (Shalabi et al., 2006) and the Cochrane collaboration (Esposito et al., 2007) were not able to find any clinical evidence supporting the positive effect of increasing surface roughness on osseointegration. Although it has been suggested that a moderate rougness value (Ra, between 1 and 2 m) is optimal for bone-implant interactions (Wennerberg & Albrektsson, 2000), there is still no suitable roughness to specific metallic biomaterials. The effect of surface topography, especially the microroughness, on bone response around dental implants has been reviewed intensively elsewhere (Cooper, 2000; Oshida, 2007; Wennerberg & Albrektsson, 2009).
From an in vitro standpoint, the response of cells and tissues at implant interfaces can be affected by the surface topography (Gaydos et al., 2000; Moore et al., 2000). Culture models provide better conditions to test the direct interactions between the implant surfaces and cells. Surface roughness in the range from 1 to 10 m influences the interface biology, since it is the same order in size of various cell types responsible for bone-implant healing. The literature contains plentiful information about the effects of micro-scale textures on cells and tissues. However, due to multiplicity of roughening protocols and cell culture models in literature, it is difficult to draw an ultimate conclusion about the effect of microroughness on cellular activities. In order to obtain ideal cell colonization on the surface, an increase in cell proliferation is an important parameter when evaluating the effectiveness of surface micro-morphology. There are limited studies that documented better cellular proliferation on surfaces with microrough topography (Deligianni et al., 2001; Marinucci et al., 2006). Mustafa et al. (2001) blasted the machined titanium surfaces with 63-90 μm, 106-180 μm and 180-300 μm TiO2 particles and obtained test models having different microtopographies. They showed that on all microrough surfaces the cell proliferation was better compared with machined surfaces and they found an insignificant increase in cell proliferation parallel to increasing roughness. However, most studies until now argued that surface microroughness influenced cell proliferation negatively (Anselme et al., 2000a; Linez-Bataillon, 2002; Sader et al., 2005). Anselme et al. (2000b) mechanically polished and sand-blasted Ti-6Al-4V surfaces with 500 μm or 3mm alumina particles, so they created surfaces having increased roughness values. They documented that increasing roughness caused a significant decrease in cell proliferation and they based this negative correlation upon the change in surface elemental composition (AlOx contamination) after blasting with alumina particles. However, there are also studies that didn’t found any negative relation between alumina contamination and biological response (Wennerberg et al., 1996).
To evaluate the effect of surface microtopography on osteogenic cell functions, Boyan and her colleagues (Boyan et al., 1998, 2001; Schwartz et al. 2001a) established an experimental study design that consists of pure titanium disks having increased roughness values. They produced dual acid-etched (PT), dual acid–etched and corrundum-blasted (SLA) and titanium plasma sprayed (TPS) test groups. Other researchers (Lossdörfer et al., 2004) that were using the same protocol revealed that on rough surfaces such as SLA and TPS, the cell attachment and 3H-tymidin incorporation, an important finding of cell proliferation, was decreased compared with smoother PT surfaces. Kieswetter et al. (1996) asserted that this decrease in cell proliferation was a sign of a more differentiated cellular phenotype in culture, as described in the theory by Lian and Stein (1992). To test this hypothesis, Boyan et al. (2002) cultured fetal rat calvarial cells on PT, SLA and TPS surfaces and documented that after 14 days of culture on rough surfaces, in spite of decreased cell proliferation, the bone nodule formation and ALP specific activity which is an early marker of osteogenic differentiation was significantly increased. Besides, it has been shown that on surfaces with rough microtopographies, osteoblasts secrete factors, such as osteoprotegerin (OPG), receptor activator of nuclear factor kappa B ligand (RANKL), prostoglandins (PGE1 and PGE2) and TGF-β1, that enhance osteoblast differentiation while decreasing osteoclast formation and activity (Lossdörfer et al., 2004). These results indicate that on rough surfaces osteoblasts exhibit a more differentiated phenotype, even though the proliferation is negatively affected.
The mechanism by which topography influences osteoblast differentiation appears to be mediated by integrin signaling (Olivares-Navarrete et al., 2008) and mitogen-activated proteine kinase (MAPK) pathways (Schwartz et al., 2001b). The topography has also an effect on subsequent expression of transcription factors, ECM protein genes and cytokines (Balloni et al., 2009; Marinucci et al., 2006). However, the in vivo interaction of osteogenic cells with an implant surface is different from the in vitro culture studies. Therefore, two essential aspects should also be taken into consideration when testing titanium surfaces under in vitro conditions. First, the osteoblast-surface interaction studies do not provide information about the role of surface topography on the initial platelet activation within the associated blood clot. The platelet adhesion on the surface and the subsequent release of platelet-derived growth factors is critical for the recruitment of bone-forming cells into the interface. Park et al. (2001) have demonstrated, that platelet adherence, platelet-derived microparticle (MP) formation and P-selectin expression were enhanced on microrough surfaces, and suggested that this increased activation of platelets may be the reason for up-regulation of osteogenic responses during bone healing. Second, the initial adsorption of blood-derived molecular factors influences the attachment of osteogenic cells on titanium implants. The plasma protein adsorption behaviour is also affected by the surface topography. The effect of surface roughness on protein adsorption was investigated by determining the adsorption of bovine serum albumin (BSA) and fibronectin, from single protein solutions on rough and smooth Ti-6Al-4V surfaces (Deligianni et al, 2001). It was reported that the rough substratum bound a higher amount of total protein (from culture medium supplied with 15% serum) and fibronectin (10-fold) than did the smooth one. Sela et al. (2007) showed that the increase of the 3D surface area through acid-etching and blasting of titanium has resulted in increased adsorption of plasma proteins.
In general, a huge number of animal investigations also agree on the positive effect of surface roughening protocols on osseointegration. Numerous animal models and surgical protocols were performed to evaluate the bone response around dental implants. Until now, the majority of the studies have focused on commercially available implant surface designs and compared them mostly with machined controls. Various microrough profiles established by different surface methodologies, such as blasting, etching, blasting/etching, plasma spraying and oxidation, were found to be stronger integrated in bone when compared with machined surfaces (Wennerberg & Albrektsson, 2009). Unfortunately, it is very difficult to compare different studies, because wound healing conditions and kinetics differ between animal models. Also, the topographical parameters vary between different microrough surfaces among previously published studies; therefore, it is impossible to obtain and establish an appropriate roughness profile of titanium for better osseointegration. Besides, it should be not neglected that procedures for the establishment of microroughness also result in changes in the surface chemistry and hence it makes the evaluation of the unique effect of roughness on the bone response (Wennerberg & Albrektsson, 2009).
3.2. Physicochemical composition of titanium surfaces
Beside topographical features of titanium surfaces, the chemistry, wettability and charges are also important parameters affecting the extent of bone response (Elias et al., 2008). If a titanium implant is inserted into the host bone, titanium dioxide should be considered as an interacting surface, rather than its bulk. Due to high affinity to oxygen, a very thin oxide film is formed on titanium when exposed to air (Kasemo & Gold, 1999). Titanium dioxides are different from the metallic Ti and have properties similar to ceramics. The biocompatibility of titanium is therefore the result of the chemical stability and corrosion resistance of its dense and protective oxide film (Healy & Ducheyne, 1992). The crystal structure of this film is believed to be important for the success of implant integration. Although marketed biomedical titanium implants mostly exhibit anatase or rutile type crystal phase, amorphous structure can be also formed on titanium following electrochemical procedures. For example, Sul et al. (2001, 2005) investigated several microarc oxidized implant surfaces having different crystal structures (amorphous, anatase, anatase-rutile mixture) in rabbit tibia model. Both anatase and anatase/rutile surfaces exhibited better torque resistance values compared with amourphous ones. It has been stated that, beside the titania crystal structure, also the microporous topography and oxide thickness has a positive effect on the positive outcome of bone response. These results were also confirmed by other in vitro studies. Anatase or rutile surfaces showed better cellular responses, such as increased adhesion, proliferation, expression of osteoblastic markers (procollagen type I peptide, osteocalcin and alkaline phosphatase) and mineralized nodule formation, compared with amorphous ones (Li et al., 2004; Saldana et al., 2005).
While the crystal structure of titanium can be changed following various thermal and non-thermal treatments, the wettability characteristics of the surface is also altered with respect to this modification. Also, various attempts have tried to find an optimal surface wettability profile for achieving better bone response. According to the literature, highly hydrophilic surfaces are proposed to be more desirable than hydrophobic ones (Junker et al., 2009; Schwarz et al., 2009). Preliminary in vitro studies indicated the hydrophilic nature of titanium surfaces significantly influences the cell differentiation and growth factor production positively (Rausch-Fan et al., 2008; Zhao et al., 2007). Besides, animal studies also shown that on hydrophilic surfaces osseointegration can be established at an early period (Bornstein et al., 2008; Buser at al., 2004; Schwarz et al., 2007). However, there are also contradictory results from other in vitro studies. For example, Kern et al. (2005) sintered titanium surfaces at 750° C for 90 min to transform amorphous crystal structure into anatase and found no significant differences in osteoblast adhesion despite of changes in hydrophilicity and oxide structure. Le Guehennec et al. (2008) cultured MC3T3-E1 cells on alumina blasted, biphasic calcium phosphate blasted (BCP-Ti) and commercial SLA surfaces and were not able to demonstrate any significant differences between hydrophobic SLA and hydrophilic BCP-Ti surfaces in their MTS and ALP assays. Bauer et al. (2008) cultured rat MSCs on nanotubular titanium surfaces having different wettability characteristics and found an increased cell attachment on super-hydrophobic surfaces compared with super-hydrophilic ones. Due to the ambiguous results in the literature, it is difficult to state that the hydrophilicity of surface is the only reason for enhanced outcomes. The microtopography, chemistry and wettability must be taken together into consideration.
4. Novel trends at the bone-implant interface
4.1. Biomimetic coating of titanium surfaces with calcium phosphates
Beside its excellent biocompatibility and biomechanics, titanium itself is not bioactive. To overcome the limited bioactivity of titanium and to improve the de novo bone formation around these implants, research was focused on preparing calcium phosphate (Ca-P) coatings on titanium and its alloys. It has been well established that the Ca-P based coating of titanium favours the bone response compared with the uncoated titanium (Chang et al., 1999a; Wheeler, 1996). Additionally, Ca-P based surfaces bind more attachment proteins, such as fibronectin and vitronectin, for the integrin mediated binding action of osteoprogenitors compared to titanium surfaces (Kilpadi et al., 2001). Several techniques were described for the deposition of Ca-P coatings on titanium implants, including ion beam deposition, plasma spraying, sol-gel methods, laser deposition, radiofrequency sputtering, biomimetic deposition and electrostatic spray deposition (Ong & Chan 2000). Among these procedures, plasma spraying is the most popular method for the deposition of Ca-P coatings on titanium implants. But this technique has some drawbacks, including the difficulty in controlling the coating structure, the weakening of the coating-implant interface and the high temparature of the deposition process (Cofino et al., 2004; Dalton & Cook, 1995)
Figure 2.
Top and cross sectional SEM images of biomimetic Ca-P coatings
Biomimetic calcium Ca-P coating procedure, first introduced by Kokubo et al. (1990), is one of the novel approaches for preparing bioactive calcium phosphate layers on titanium surface. This technique involves the precipitation of bone like apatite crystals from a simulated body fluid (SBF) onto titanium surfaces under physiological temperature (37ºC) and pH (7.4) that mimics the normal conditions in human blood plasma. To shorten the immersion period of the substrate within calcium phosphate containing solution, the method was further revised by a group of investigators (Barrere et al., 2001; Liu et al., 2004) Thus, a calcium phosphate lattice can be formed on titanium surfaces in order to provide osteoconductive properties to the substrate (Fig. 2.). Another advantage of this simple and economical procedure is that the biomimetic surface acts as a tissue-engineering scaffold and this process can be combined with deposition of signalling molecules, like growth factors and bone morphogenetic proteins (Liu et al., 2004, 2007; Ramazanoglu et al., 2011).
4.2. Biomolecular coatings of titanium surfaces
Beside the topographical and physicochemical modifications, biochemical approaches to immobilize different bioactive molecules, peptides, proteins and others on dental implants attracted the interest of many scientists. The main idea behind these methodologies was as follows: (1) to eliminate the adsorption of proteins that would result in the adhesion of unspecific cells leading to fibrous integration; (2) to enhance the specific attachment of osteogenic cells for the establishment of a tight bone-implant interface; (3) to provide integrin-mediated signals for provoking the bone healing mechanisms. For this purpose, various immobilization methods were utilized, including physical adsorption (Wikesjö et al., 2008), incorporation into Ca-P lattice (Liu et al., 2004, 2007; Ramazanoglu et al., 2011), covalent attachment (Bagno et al., 2007), self-assembly of monolayers (Heijink et al., 2008) and electrochemical methods (Beutner et al., 2010). Complete description of these methods is beyond the scope of this chapter and reviewed intensively elsewhere (Beutner et al., 2010). However, the organic molecules used for bio-functionalization of titanium-based materials are of importance for orientating the tissue response. Especially, extensive studies have been performed on binding ECM proteins and their peptide sequences to titanium to promote osteogenic cell adhesion. Although the coating of titanium with a single protein has resulted in enhancement of cellular adhesion (MacDonald et al., 2004), research has mainly focused on immobilizing short cell binding motifs within these ECM molecules due to their structural integrity (Morra, 2006). In particular, the RGD motif, as discussed before, is one of the most studied protein sequence capable of promoting cell adhesion and thereby initiating intracellular signalling cascades through multiple integrins including v3 and 51 (Ruoslahti, 1996). This motif is usually covalently attached to titanium using silanization (Bagno et al., 2007) or functionalized using polymer chemistry (Tosatti et al., 2004), and has been reported to increase osteoblast attachment and proliferation (Schuler et al., 2006). While several in vivo studies (Elmengaard et al., 2005; Kroese-Deutman et al., 2005) demonstrated better osseointegration results, others did not find any significant enhancement for the RGD functionalization (Petrie et al., 2008; Schliephake et al., 2009).
Another approach for enhancing the osseointegration is the delivery signalling molecules, especially the osteogenic growth factors. The concept of coating implant surfaces with osteogenic growth factors, such as bone morphogenic proteins (BMPs), to enhance osseointegration has been documented in several studies using different delivery strategies (Becker et al. 2006; Sykaras et al. 2004; Wikesjö et al. 2008). The bone forming potential of BMPs around implants have been shown in an experimental study using an atelopeptide type-I collagen carrier as a coating (Bessho et al. 1999). However, other studies utilizing a collagen/chondroitin sulphate (CS) carrier system on titanium found an enhancement of bone volume density (BVD) and bone-implant contact (BIC) around coated implants, but they were not able to show any significant difference between bare collagen/CS and BMP integrated coatings (Schliephake et al. 2005; Stadlinger et al. 2007). Due to the variation of findings between different studies, it can be stated that there is still a need for an optimal 3D carrier on the implant surface to provide sufficient retention of BMPs at the repair site. As mentioned before, the biomimetic coating method has been shown to have the potential of being an appropriate BMP carrier on the titanium surface. It has been demonstrated that BMP-2 incorporated in calcium phosphate coatings can induce bone formation at an ectopic site and the sustained release of BMP-2 from this coating has an important effect on the osteoinductivity of the material (Liu et al. 2005). However, studies using this methodology failed to show a significant effect of biomimetic coated implants with incorporated BMP-2, VEGF or their combination on osseointegration, and it has been stated that an ideal dose of BMP-2 or VEGF, which resembles the growth factor release from natural bone matrix should be achieved for enhancing the osseointegration (Liu et al. 2007; Ramazanoglu et al., 2011).
4.3. Nanotopographical modification of titanium surfaces
The structures encountered by osteoblasts in the human body are not only in micrometer scale, since bone is made up by nanostructures. Thus, there is a need to produce better implant materials having also nanometer roughness. Several studies have suggested that nanophase materials produced from various chemistries, such as metals, polymers, composites and ceramics, improved cellular activities when compared with conventional microrough materials (Gutwein & Webster, 2004; Webster & Ejiofor, 2004). Nanobiomaterials have an increased percentage of atoms and crystal structures, and also provide a higher surface area than the conventional ones. Thus, nanoscale surfaces possess high surface energy leading to increasing initial protein adsorption that is very important in regulating the cellular interactions on the implant surface. Webster et al. (2001) suggested increased osteoblast adhesion on nanophase materials. Numerous studies have shown that osteoblasts cultured on nanophase biomaterials exhibited better osteogenic behaviour, including adhesion, ECM production and mineralization, than on conventional materials (Elias et al., 2002; Price et al., 2003).
In recent years, several methods have been also developed to produce nanoscale structures on titanium surface. While irregular nanomorphologies can be established using solution chemistry (Mendonça et al., 2010), the electrochemical anodization of titanium is the most popular and novel strategy to produce controlled structures (including nanotubes, pillar-like nanostructures, and nanodots) on implant surfaces for load bearing approaches (Oh et al., 2006; Sjöström et al., 2009). Especially, the titania nanotube arrays are one of the most promising candidate of titanium nanosurfaces for dental implantology (Fig. 3.). Several in vitro studies have demonstrated that cells cultured on these nanotubular surfaces showed higher adhesion, proliferation, ALP activity and bone matrix deposition (Oh et al., 2006; Popat et al., 2007a).
Figure 3.
Top and cross sectional SEM images of titania nanotubes
These increased in vitro cellular activities for titania nanotubes also translated to in vivo bone bonding. Nanotubular surfaces significantly improved bone bonding strength by as much as nine-fold compared with gritblasted surfaces, and histological analysis revealed greater bone-implant contact and collagen type I expression confirming the better in vivo behaviour of titania nanotubes (Bjursten et al., 2008; von Wilmowsky et al., 2008). It has been also shown that various nanomorphological features of titania nanotubes, such as length, diameter, wall thickness, have a major impact on the cellular reponses, providing the evidence that cells are susceptible to nanoscale dimesions (Brammer et al., 2009; Park et al., 2009). Besides, nanotubular structures on titanium provide a suitable infrastructure for loading and subsequent releasing of antibiotics (Aninwene et al., 2008; Popat et al., 2007b) or for immobilizing biosignalling molecules for better osseointegration (Balasundaram et al., 2007). However, there is still a need for additional studies that would optimize the fabrication of nanotubes for better bioactivity.
5. Future trends and concluding remarks
Nowadays, patients can be treated dental implants with a success rate above 97 %. Although novel approaches were able to accelerate and enhance the osseointegration, the healing limits of the body, which make the immediate loading challenging, should not be neglected. Osseointegrated or ankylotic titanium implants don’t behave like natural teeth. Since they lack a periodontal ligament, they only had tenth of the mobility of the natural teeth (Schulte, 1995). Axial and horizontal loads bellow a subjective tolerance limit can be compensated by the natural periodontium, but such loads on osseointegrated implants would lead to local disruption of the bony interface. Additionally, it has been reported that the defensive capacity of the peri-implant tissue against bacterial invasion is inferior to that of the natural tooth, that make them more prone to bone loss (Chang et al., 1999b). A third disadvantage of the osseointegrated implant is the absence of a periodontal neurophysiological mechanoreceptive system for the biocybernetic control of the stomatognatic system (Jacobs & Van Steenberghe, 2006).
Considering these drawbacks, establishment of a periodontal ligament surrounding an implant, termed as bio-root, would provide the ideal condition for implant-supported treatments in future. To overcome the above mentioned disadvantages of the dental implants, several in vivo experiments attempted to create a periodontal ligament around these implants by placing them adjacent to retained tooth roots (Urabe et al., 2000; Warrer et al., 1993). Although they were able to partially regenerate the periodontal ligament consisting of cementum, periodontal ligament and alveolar bone, the application of these methods in patients seems to be impossible due to technical and physical factors. Furthermore, several studies have reported that periodontal ligament cells cultured on titanium implants can produce a periodontal ligament-like tissue when placed in the jaws of animals (Choi, 2000; Gault et al., 2010; Lin et al., 2011). Although it has been shown that generating a periodontal-like tissue around implants may be experimentally possible, also in human trials (Gault et al., 2010), approaches until now were not able to innovate a predictable and feasible method for producing dental implants with periodontal-like ligament.
Furthermore, gradient functional concept (GFC) on materials and structures has been receiving special attention not only in industrial applications, but in dental as well as medical fields. Particularly, when such structures and concepts are about to be applied to implants, its importance becomes more clinically crucial. For example, the majority of implant mass (implant core portion) should be strong and tough, so that occlusal force can be smoothly transferred from the placed implant to the receiving hard tissue. However, the surface (implant case portion) needs to be engineered to exhibit some extent of roughness. From such macro-structural changes from bulk core to the porous case, again the structural integrity should be maintained. The GFC can also be applied for the purpose of having a chemical (compositional) gradient. Ca-, P-enrichment is not needed in the interior materials of the implants. Some other modifications related to chemical dressing or conditioning can also be utilized for achieving gradient functionality on chemical alternations on surfaces as well as near-surface zones (Oshida, Y.; 2007).
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Introduction",level:"1"},{id:"sec_2",title:"2. Healing around the endosseous implant",level:"1"},{id:"sec_3",title:"3. Surface treatments for enhanced osseointegration",level:"1"},{id:"sec_3_2",title:"3.1. Topographical features of titanium surfaces",level:"2"},{id:"sec_4_2",title:"3.2. Physicochemical composition of titanium surfaces",level:"2"},{id:"sec_6",title:"4. Novel trends at the bone-implant interface",level:"1"},{id:"sec_6_2",title:"4.1. Biomimetic coating of titanium surfaces with calcium phosphates",level:"2"},{id:"sec_7_2",title:"4.2. Biomolecular coatings of titanium surfaces ",level:"2"},{id:"sec_8_2",title:"4.3. Nanotopographical modification of titanium surfaces ",level:"2"},{id:"sec_10",title:"5. Future trends and concluding remarks",level:"1"}],chapterReferences:[{id:"B1",body:'AbrahamssonI.ZitzmannN. U.BerglundhT.WennerbergA.LindheJ.2001Bone and soft tissue integration to titanium implants with different surface topography: an experimental study in the dog. 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L.1996Eight-year clinical retrospective study of titanium plasma-sprayed and hydroxyapatite-coated cylinder implants. The International Journal of Oral and Maxillofacial Implants, 1133403500882-2786'},{id:"B150",body:'WikesjöU. M.QahashM.PolimeniG.SusinC.ShanamanR. H.RohrerM. D.WozneyJ. M.HallJ.2008Alveolar ridge augmentation using implants coated with recombinant human bone morphogenetic protein-2: histologic observations. Journal of Clinical Periodontology, 3511100110100160-0051X'},{id:"B151",body:'YamagamiA.YoshiharaY.SuwaF.2005Mechanical and histologic examination of titanium alloy material treated by sandblasting and anodic oxidization. The International Journal of Oral Maxillofacial Implants, 20148530882-2786'},{id:"B152",body:'YangY.CavinR.OngJ. L.2003Protein adsorption on titanium surfaces and their effect on osteoblast attachment. Journal of Biomedical Materials Research Part A, 6713443491549-3296'},{id:"B153",body:'ZhaoX.LiuX.DingC.2005Acid-induced bioactive titania surface. Journal of Biomedical Materials Research Part A\n\t\t\t\t\t7548888941549-3296'},{id:"B154",body:'ZhaoG.RainesA. L.WielandM.SchwartzZ.BoyanB. D.2007Requirement for both micron- and submicron scale structure for synergistic responses of osteoblasts to substrate surface energy and topography. Biomaterials, 2818282128290142-9612'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Mustafa Ramazanoglu",address:"",affiliation:'
Istanbul University/Department of Oral Surgery, Turkey
Istanbul University/Department of Oral Surgery, Turkey
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\n
1. Introduction
\n
The treatment of cancer has witnessed major advances which have resulted from the recent revolution in medical interventions. It is commonly observed in clinical settings that the same doses of medication cause considerable variations in efficacy and toxicity across human populations [1, 2]. These variations can lead to unpredictable life-threatening or even lethal adverse effects in cases receiving the medications [3, 4]. Genetic factors are important determinants for drug efficacy and toxicity since the interindividual variability in drug response cannot be explained only by physiological, life style, age, comedication, etc. factors (Figure 1). Pharmacogenetics is the study of how genetic inheritance influences response to drugs. The term “pharmacogenetics” was coined in the 1950s, with the discovery that there is an inherited basis for differences in the disposition and effects of drugs and xenobiotics [5]. The studies found that antimalarial drugs and certain foods (soy beans) cause hemolytic reactions in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The term pharmacogenomics and pharmacogenetics are often used interchangeably. Pharmacogenetics was first used in the literature in 1997 and ever since the developments in this field have been greatly facilitated by rapid progress in molecular technology, in particular, high throughput DNA sequencing, microarrays and genotyping [6].
\n
Figure 1.
Inter-individual variations in drug response.
\n
Cancer pharmacogenetics has started getting a lot of attention due to the potential for individualisation of cancer therapy, minimizing toxicity, while maximizing efficacy. Cancer pharmacogenetics allows identification of patients at risk for severe toxicity, or those likely to benefit from a particular treatment and thus helps us move toward the ultimate goal of individualized cancer therapy. There are significant differences between cancer and other disease pharmacogenomics. In cancer, both germline genome of the patient and the somatic genome of the tumor are involved. The former is responsible for the inter-individual inherited genetic differences while the latter is due to accumulation of acquired somatic mutations resulting in inconsistent responses. Cancer pharmacogenomics also faces the problem of conducting human studies, availability of healthy volunteers for receiving cancer drugs and multigenic control of drug response. Table 1 lists some of the major biomarkers which are associated with cancer treatment toxicities while Table 2 lists some of the biomarkers associated with cancer treatments mentioned in US FDA-approved drug labels.
\n
\n
\n
\n
\n
\n
\n\n
\n
Gene
\n
Significant polymorphisms
\n
Target drug
\n
Action
\n
Clinical relevance
\n
\n\n\n
\n
TPMT
\n
TPMT*2, *3A,*3B,*3C
\n
6-Mercaptopurine (6-MP)
\n
Increased levels of 6-MP
\n
Myelotoxicity
\n
\n
\n
DPD
\n
DPD*2A
\n
5-FU
\n
Increased levels of 5-FU
\n
Neurologic, hematological toxicities
\n
\n
\n
UGT1A1
\n
UGT1A1*28
\n
Irinotecan
\n
Increased levels of SN-38
\n
Severe diarrhea, neutropenia
\n
\n
\n
GST
\n
Deletion, Ile105Val
\n
Platinum agents
\n
Increased DNA damage
\n
Drug toxicity increased
\n
\n
\n
XRCC1
\n
Arg194Trp, Arg280His, Arg399Gln
\n
Platinum agents
\n
Increased DNA damage
\n
Drug toxicity increased
\n
\n
\n
ERCC1
\n
K751Q
\n
Platinum agents
\n
Increased DNA damage
\n
Drug toxicity increased
\n
\n\n
Table 1.
Pharmacogenetic biomarkers and their clinical impact.
The prediction of cancer treatment outcome based on gene polymorphisms is becoming a reality for many classes of chemotherapy agents, and the most clinically significant examples are discussed below.
\n
\n
2.1 Thiopurines
\n
Thiopurines are a family of drugs that includes 6-mercaptopurine (6-MTP) which is a daily component of maintenance therapy for childhood acute lymphoblastic leukemia treatment [7], thioguanine and azathioprine. There are three major metabolic pathways for 6-MTP namely activation of 6-MTP into 6-TGN (activating and cytotoxic route for thiopurines) by hypoxanthine guanine phosphoribosyl transferase (HGPRT), inactivation of 6-MTP into thiouric acid via oxidation catalyzed by xanthine oxidase and inactivation of 6-MTP via S-methylation of the thiol moiety in the liver and red blood cells by thiopurine methyltransferase (TPMT). This methylation shunts the active drug away from TGN formation. Thiopurines are inactive prodrugs that require metabolism to thioguanine nucleotides (TGN) to exert cytotoxicity by incorporation of TGN into DNA. This activation is catalyzed by methylation by thiopurine methyltransferase (TPMT) of the thiopurine agents azathioprine, mercaptopurine, and thioguanine [7, 8], thereby shunting drug away from TGN formation. Genetic variants present in TPMT may alter the treatment response in cases receiving chemotherapeutic drugs. TPMT exhibits huge variations in enzyme activity with a major portion of population (90%) exhibiting high activity while about 10% have intermediate activity, and 0.3% have low or no detectable enzyme activity [9, 10]. Out of several genetic variants, TPMT*2 (238G>C), *3A (460G>A and 719A>G), *3B (460G>A), and *3C (719A>G) account for about 95% of intermediate or low enzyme activity cases [7, 11, 12, 13, 14]. Caucasians have more prevalence of TPMT polymorphisms and a trimodal distribution of TPMT enzyme activity while southeast Asians have less prevalence and a unimodal distribution [15, 16, 17].
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Several studies have shown that TPMT-deficient patients are at very high risk of developing severe hematopoietic toxicity if treated with conventional doses of thiopurines [18, 19]. Studies have also been carried out to show that patients who are heterozygous at the TPMT locus are at intermediate risk of dose-limiting toxicity [20, 21]. In one of our studies, a poor treatment response was observed in head and neck cancer patients receiving chemotherapy with cisplatin and 5-FU which might be due to the higher intracellular concentration of cisplatin due to lower or intermediate TPMT enzyme activity [22]. Liu et al. [23] examined primary erythrocyte TPMT activity in children with leukemia in a genome-wide association study and found that TPMT was the only gene that reached genome-wide significance. In another study of 67 patients treated with azathioprine for rheumatic disease, 6 patients (9%) were heterozygous for mutant TPMT alleles, and therapy was discontinued in 5 of 6 patients because of low leukocyte count within 1 month of starting treatment [20].
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2.2 5-Fluorouracil (5-FU)
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5-Fluorouracil (5-FU) is a uracil analog that is widely used to treat solid tumors, such as colorectal and breast cancer and requires activation to 5-fluoro-2-deoxyuridine monophosphate (5-FdUMP). At least 85% of 5-FU is inactivated by dihydropyrimidine dehydrogenase (DPD) to dihydrofluorouracil in the liver. [24] 5-FdUMP acts by inhibiting the tumor cell replication via inhibition of thymidylate synthase (TS), an enzyme that is required for de novo pyrimidine synthesis. DPD inactivates 5-FU in the liver and has huge differences in activity among individuals leading to excessive amounts of 5-FdUMP in patients with low activity which causes gastrointestinal, hematopoietic, and neurological toxicities [25, 26, 27, 28, 29, 30, 31, 32].
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The DPD gene has several reported polymorphisms associated with reduced DPD activity [32, 33]. In general, 3–5% of individuals are heterozygous carriers of mutations that inactivate DPD, and 0.1% of individuals are homozygous for mutations that inactivate DPD [27, 34, 35, 36]. DPD*2A allele is caused by a G>A transition at a GT splice donor site flanking exon 14 of the DPD gene (IVS14+1G>A). A decreased DPD activity has been found to be associated with severe or fatal toxicity from standard doses of 5-FU [37]. Another mutation at codon 534 leads to a 1601G>A nucleotide change. In one of our study, head and neck cancer patients exhibited a poor treatment response which had IVS14+1G>A genetic variant. [22] Similarly, it was also reported that IVS14+1G>A was associated with increased toxicity and poor treatment response in patients of invasive ductal carcinoma and head and neck cancer. Zhao et al. [38] found that DPD variant c.85T>C (rs1801265, DPYD*9A) was associated with treatment outcome in acute lymphoblastic leukemia.
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2.3 Irinotecan
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Irinotecan, a topoisomerase I inhibitor, is used to treat various solid tumors, and requires activation by carboxylesterase to its active metabolite, SN-38. The toxicities associated with Irinotecan, namely diarrhea and leucopenia, are due to increased levels of SN-38. UDP-glucuronosyltransferase 1A1 (UGT1A1) present in liver metabolizes SN-38 by glucuronidation to produce the more polar and inactive SN-38 glucuronide, which is removed in the bile and urine [39]. In chemotherapy, a decreased rate of glucuronidation has been shown to be an important factor in prediction of toxicity. The rate of glucuronidation is reduced as a consequence of reduced transcription rate due to abnormal dinucleotide repeat sequences (5–8 repeats) within the TATA box of the UGT1A1 gene promoter [40]. An inverse relationship exists between the number of TA repeats and the UGT1A1 transcription rate. The variant allele UGT1A1*28 results from the presence of seven repeats, instead of the wild-type number of six. The UGT1A1*28 allele is associated with reduced UGT1A1 expression, and leads to reduced SN-38 glucuronidation [41].
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(TA)n TAA promoter polymorphisms are more frequent in Caucasians than in Asians which have more missense polymorphisms in the exons [42]. Studies have shown that the UGT1A1*28 allele leads to significantly increased amounts of the active metabolite SN-38, and consequently an increased chance of developing side effects such as diarrhea and leukopenia during irinotecan therapy. [41, 43]. In one study of 20 patients with solid tumors treated by irinotecan, severe toxicity was observed in UGT1A1*28 heterozygotes and homozygotes [41]. In another retrospective study of 118 cancer patients treated with irinotecan, a significant proportion of the 26 patients suffered from severe diarrhea or neutropenia. Upon examination, all 26 were UGT1A1*28 homozygotes or heterozygotes (15 and 31%, respectively), whereas only 3% UGT1A1*28 homozygotes and 11% UGT1A1*28 homozygotes were found among 92 patients without toxicity [43]. Font et al. [44] reported that 34% of non-small cell lung carcinoma (34%) patients with the common genotype achieved disease control (partial response or stable disease) compared with 13 of 24 patients (54%) with the variant genotypes.
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2.4 Platinum agents
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Platinum agents like cisplatin, carboplatin and oxaliplatin act by inhibiting cell replication as a result of formation of DNA adducts. However, sometimes the effect of platinum agents is compromised as a result of decreased drug accumulation, detoxification, reduced or no DNA adduct formation and an increased activity of DNA repair system. One of the factors that can influence response to platinum chemotherapy agents is polymorphisms in glutathione (GSH)-dependent enzymes. Glutathione-S-transferases (GSTs) catalyze the conjugation of GSH to platinum agents, forming less toxic and more water-soluble conjugates. There are five subclasses of the GST family (GSTA1, GSTP1, GSTM1, GSTT1, and GSTZ1) [61] that influence cytotoxicity to a variety of chemotherapeutic agents [45].
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Several genetic variants exist in the GSTs which may lead to complete absence (GSTM1 and GSTT1) or partially deficient enzyme (GSTP1) activity. Ethnic differences are reported in the distribution of null or variant allele frequencies of GSTM1, GSTT1 and GSTP1. Studies from our laboratory have shown association of polymorphism in drug metabolizing cytochrome P450s (CYPs) and GSTs with head and neck cancer [46]. Studies also revealed significant increase in head and neck cancer risk in cases with null genotypes of GSTM1 or GSTT1, though inconsistent reports are also available. Likewise, no consistent data is available on the association of GSTP1 polymorphism with head and neck cancer risk [47]. Further, site specificity is also reported in the expression of GSTs in the squamous mucosa of head and neck which may lead to the differences in the susceptibility when analyzed according to the tumor location. An association between the GSTM1 and GSTT1 null genotype for non-laryngeal upper aero-digestive tract (UADT) or oral cancer risk was reported in smokers or tobacco chewers. In contrast, no site specific differences in the distribution of GST variant forms have also been observed in few studies [48].
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The null genotypes for GSTM1 or GSTT1 were associated with a reduction in risk of relapse in several tumor types treated with chemotherapy such as acute lymphoblastic leukemia, acute myeloblastic leukemia, breast cancer, ovarian cancer, and lung cancer. In addition to null phenotypes, single nucleotide polymorphisms (SNPs) also affect response to chemotherapy and survival of patients as seen in breast cancer patients with an I105V SNP in the GSTP1 gene. Women with the low-activity VV genotype had better survival upon cyclophosphamide-based chemotherapy [49]. Dasgupta et al. [50] compared the role of the I105V genotype in multiple myeloma treated with standard or high dose chemotherapy and found that the patients with the 105VV homozygote allele had an improved progression free survival. The substitution of isoleucine with valine at position 105 reduces enzyme activity against alkylating agents. Stoehlmacher et al. [51] showed that SNP in GSTP1 was associated with overall survival in 107 patients with metastatic colorectal cancer who received 5-FU/oxaliplatin combination chemotherapy. In this study, 10 patients (9%) were homozygous for valine, 45 patients (42%) were heterozygous, and 52 (49%) were homozygous for isoleucine. Interestingly, GSTM1 and GSTT1 mutations that abolish enzyme activity had no predictive power for patient outcome.
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Anticancer agents act by causing DNA damage in tumor cells which is subsequently repaired by the DNA repair machinery of the cell. Thus, more the active DNA repair system, less will be the treatment outcome. XRCC1 is a prominent gene involved in DNA repair via the base excision repair pathway which repairs single strand breaks through interaction of XRCC1 with PARP-1, PNK, Polb, and Lig3a [52]. XRCC1 has several genetic variants out of which the prominent ones are Arg194Trp on exon 6, Arg280His on exon 9, and Arg399Gln on exon 10 [53]. A study conducted by Quintela-Fandino et al. [54] in head and neck cancer cases found that XRCC1 Gln/Gln was responsible for 61.5% of cases with complete response. The role of XRCC1-Gln399Gln genotype was also investigated by Duell et al. [55]. It was reported that the allele results in high rate of sister chromatid exchange after exposure to ionizing radiation in human lymphocytes. There are also reports which suggest the role of XRCC1 G28152A Arg399Gln polymorphism in development of lower grade of fibrosis as a result of radiotherapy in 60 nasopharyngeal cancer patients [56]. Mahimkar et al. [57] studied clinical outcome in advanced oral cancer patients treated with postoperative radiotherapy and did not observe a significant association between polymorphisms of XRCC1 and clinical outcome. Zhai et al. [58] observed that Codon399 Gln/Gln allele was associated with a higher tumor regression ratio after radiotherapy for primary nasopharyngeal neoplasm and metastatic lymph nodes. Ghazali et al. [59] conducted a systematic review and found that risk of severe acute mucositis was associated with the G allele of XRCC1 (1196A>G) in head and neck cancer patients treated with radiotherapy alone or chemotherapy.
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Excision-repair cross-complementing 1 (ERCC1) gene encodes a helicase which is required for the nucleotide excision repair pathway. Several polymorphisms in ERCC1 which result in differing DNA repair capacities have been identified. Lowered mRNA production was observed as a result of a silent C118T SNP in ovarian carcinoma cell lines [60]. The TT genotype resulted in a reduction in codon usage by half with a reduction in ERCC1 mRNA production and therefore be associated with reduced DNA repair capacity [61]. Platinum is a standard chemotherapy for advanced non-small cell lung cancer (NSCLC), and platinum-induced DNA lesions are repaired by ERCC1. Studies have shown that patients homozygous for the ERCC1 118C allele demonstrated a significantly better survival. In colorectal carcinoma patients treated with 5-fluorouracil and oxaliplatin, the K751Q SNP of the ERCC2 (Xeroderma pigmentosum group D gene, XPD) determined in peripheral blood lymphocytes was of prognostic relevance. The patients having KK homozygotes responded more frequently to chemotherapy and lived significantly longer than did heterozygotes or QQ homozygotes [62]. Time to progression was significantly higher in cisplatinum-treated patients with non-small cell lung cancer harboring the K751Q ERCC2 genotype than those harboring the K751K genotype. However, contradictory results on the association of ERCC2/XPD variant alleles with decreasing overall survival of non-small cell lung cancer patients after cisplatinum-based therapy were also reported [63]. A nonsynonymous SNP, altering a lysine to glutamine at codon 751 of the XPD protein, was significantly associated with treatment outcome in patients with metastatic colorectal cancer [62].
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3. Pharmacogenetics: challenges and next generation approaches
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The current pharmacogenetics approaches face many stumbling blocks. Candidate gene-based approaches do not provide a reliable prediction of tumor drug response and normal tissue toxicity because of a lack of understanding of the precise role of all participating factors. Genome wide association study provide a more robust platform for pharmacogenetic analysis as has been demonstrated by Watters et al. [64]. A number of other issues plague SNP genotyping in the clinical settings such as quality control which is due phenotypic heterogeneity, a long duration involved in validation of pharmacogenetic markers in experimental settings, the combined effects of many low-risk polymorphisms, selection of the most appropriate panel of SNPs, analyzing the correlation between genotype, gene expression, and enzyme activity, criteria for risk assessment and thresholds, consideration of ethnic variations as the distribution and frequency of SNPs vary among different ethnic groups which makes it difficult to extrapolate the findings of one group on another [65]. Newer targeted therapies are also gaining popularity. Trastuzumab (herceptin), a humanized recombinant monoclonal antibody (IgG) targets Human Epidermal Growth Factor Receptor 2 (HER2), Gefitinib (Iressa) inhibits the tyrosine kinase activity of the Epidermal Growth Factor Receptor, Bevacizumab (Avastin) is an anti-angiogenesis agent, the addition of which to standard chemotherapy regimens has shown improved response rates and survival rates in the treatment of metastatic colorectal cancer [66]. Likewise, Cetuximab (Erbitux), a monoclonal antibody, targeting EGFR has also shown promising results in colorectal cancer and head and neck cancers.
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Future developments in some key areas will play a critical role in deciding the overall influence of pharmacogenetics data on therapeutic decisions. Improvements are needed in genome-wide technologies such as development of gene expression arrays, high throughput technologies, SNP chips, genome-wide scans which could potentially identify previously unidentified, functionally important candidate genes and SNPs. Mouse models could be used for genome-wide scans in offspring from phenotypically distinct mice from resistant and susceptible strains. Knockout and transgenic techniques could also be used for establishing the key elements that contribute to drug response and disposition. Candidate gene approach could be enhanced by knowledge gained from genome wide techniques and by incorporating a metabolic pathway approach. The cost of SNP/genomic technology should reduce which needs to be counterbalanced by the huge costs incurred due to adverse drug reactions/toxicities. For inclusion of a genetic test into clinical practice, it must provide reliable, predictive, and actionable information that would have otherwise been unknown [67]. Before clinical implementation, strong evidence from randomized controlled clinical trials is needed.
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The future of pharmacogenetics should focus on specimen collection of both germline and tumor DNA from early and later phase clinical trials with prospectively collected efficacy and toxicity data which will be vital in the discovery and validation of pharmacogenomic associations. At next steps, genes that have undergone replication and validation should be assessed for clinical implementation. A large retrospective case-control validation and replication studies and Phase II biomarker-driven clinical trials may allow for a more efficient and rapid method of translation from bench to bedside.
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4. Conclusions
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The major problems of cancer chemotherapy are the development of drug resistance and the severe side effects. Since many chemotherapeutic agents have modest tumor specificity, normal tissues are also damaged. This prevents the application of sufficient high doses of drugs to eradicate the less sensitive tumor cell populations. Thereby, tumors develop drug resistance that leads to treatment failure and fatal consequences for patients. Genetic variations in genes have explained a great deal of interindividual variation in response and toxicity of anticancer drugs. Cancer treatment utilizes multiple therapeutic agents with a wide variety of toxicities, often with narrow therapeutic indices. Pharmacogenetics has the potential to revolutionize cancer therapy. Though there has been substantial success in situations where single genes play a large role in overall drug response, the future of cancer treatment lies in whole-genome approaches. Reduction of the toxicogenetic and toxicogenomic side effects has been one of the major goals in the search for new anticancer drugs and therapy protocols. SNP genotyping should be introduced into clinical settings to facilitate clinical decision making regarding treatment strategies to avoid adverse drug reactions while achieving the best drug response. Few of the studies discussed do provide a stronger scientific basis for the use of genomic information for the individualization of cancer therapy based on a patient’s genetic profile.
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Conflict of interest
The author declares no conflict of interest.
\n',keywords:"cancer, pharmacogenetics, polymorphism, chemotherapy, genetic variations",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65402.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65402.xml",downloadPdfUrl:"/chapter/pdf-download/65402",previewPdfUrl:"/chapter/pdf-preview/65402",totalDownloads:527,totalViews:0,totalCrossrefCites:0,dateSubmitted:"June 26th 2018",dateReviewed:"December 10th 2018",datePrePublished:"January 29th 2019",datePublished:"November 6th 2019",readingETA:"0",abstract:"The response of cancer patients to chemotherapy follows a very heterogeneous pattern. Pharmacogenetics is the study of inherited differences in interindividual drug disposition and effects, with the goal of selecting the optimal drug therapy and dosage for each patient. Pharmacogenetics for cancer treatment is very significant, as cancer therapies exhibit severe systemic toxicity and unpredictable efficacy. There is presence of genetic polymorphisms in the genes which code for the metabolic enzymes and cellular targets for the majority of chemotherapy agents, but to predict the outcome of chemotherapy in patients is not currently possible for most treatments. A greater understanding of the genetic determinants of drug response can revolutionize the use of many medications. By identifying the patients at risk for severe toxicity, or those likely to benefit from a particular treatment, individualized cancer therapy can be achieved for most cancer patients. The prediction of cancer treatment outcome based on gene polymorphisms is becoming possible for many classes of chemotherapy agents, and the most clinically significant examples of chemotherapy agents are discussed in the chapter. However, further studies are needed in well characterized and larger cancer populations with proper validation of pharmacogenetic markers in experimental settings before application in clinical routine diagnostics.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65402",risUrl:"/chapter/ris/65402",signatures:"Munindra Ruwali",book:{id:"8400",title:"Molecular Medicine",subtitle:null,fullTitle:"Molecular Medicine",slug:"molecular-medicine",publishedDate:"November 6th 2019",bookSignature:"Sinem Nalbantoglu and Hakima Amri",coverURL:"https://cdn.intechopen.com/books/images_new/8400.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"147712",title:"Dr.",name:"Sinem",middleName:null,surname:"Nalbantoglu",slug:"sinem-nalbantoglu",fullName:"Sinem Nalbantoglu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"245866",title:"Dr.",name:"Munindra",middleName:null,surname:"Ruwali",fullName:"Munindra Ruwali",slug:"munindra-ruwali",email:"munindraruwali@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Candidate genes",level:"1"},{id:"sec_2_2",title:"2.1 Thiopurines",level:"2"},{id:"sec_3_2",title:"2.2 5-Fluorouracil (5-FU)",level:"2"},{id:"sec_4_2",title:"2.3 Irinotecan",level:"2"},{id:"sec_5_2",title:"2.4 Platinum agents",level:"2"},{id:"sec_7",title:"3. Pharmacogenetics: challenges and next generation approaches",level:"1"},{id:"sec_8",title:"4. Conclusions",level:"1"},{id:"sec_12",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics into rational therapeutics. Science. 1999;286:487-491\n'},{id:"B2",body:'Fagerlund TH, Braaten O. No pain relief from codeine? An introduction to pharmacogenomics. Acta Anaesthesiologica Scandinavica. 2001;45:140-149\n'},{id:"B3",body:'Rothenberg ML, Meropol NJ, Poplin EA, van Cutsem E, Wadler S. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: Summary findings of an independent panel. 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Pharmacogenetics. 2002;12:555-558\n'},{id:"B38",body:'Zhao XQ, Cao WJ, Yang HP, Yang XW, Tang P, Sun L, et al. DPYD gene polymorphisms are associated with risk and chemotherapy prognosis in pediatric patients with acute lymphoblastic leukemia. Tumour Biology. 2016;37:10393-10402\n'},{id:"B39",body:'Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, Ratain MJ. Metabolic fate of irinotecan in humans: Correlation of glucuronidation with diarrhea. Cancer Research. 1994;54:3723-3725\n'},{id:"B40",body:'Innocenti F, Iyer L, Ratain MJ. Pharmacogenetics of anticancer agents: Lessons from amonafide and irinotecan. Drug Metabolism and Disposition. 2001;29:596-600\n'},{id:"B41",body:'Iyer L, Das S, Janisch L, Wen M, Ramirez J, Karrison T, et al. UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. The Pharmacogenomics Journal. 2002;2:43-47\n'},{id:"B42",body:'Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: A balanced polymorphism for regulation of bilirubin metabolism? Proceedings of the National Academy of Sciences of the United States of America. 1998;95:8170-8174\n'},{id:"B43",body:'Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H, et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: A pharmacogenetic analysis. Cancer Research. 2000;60:6921-6926\n'},{id:"B44",body:'Font A, Sánchez JM, Tarón M, Martinez-Balibrea E, Sánchez JJ, Manzano JL, et al. Weekly regimen of irinotecan/docetaxel in previously treated non-small cell lung cancer patients and correlation with uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism. Investigational New Drugs. 2003;21:435-443\n'},{id:"B45",body:'Chao CC, Huang YT, Ma CM, Chou WY, Lin-Chao S. Overexpression of glutathione S-transferase and elevation of thiol pools in a multidrug-resistant human colon cancer cell line. 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