Trends Biomater. Artif. Organs, 29(1), 86-91 (2015)
http://www.sbaoi.org/tibao
Review Article
Improving Cellular Response of Titanium Surface through Electrochemical Anodization for Biomedical Applications: A Critical Review N. Jalali1, F. Moztarzadeh1, A. Asgari2, A. Zamanian4, K.D. Verma3, M. Mozafari4,* 1
Biomaterials Group, Faculty of Biomedical Engineering (Center of Excellence), Amirkabir University of Technology, P.O. Box 15875-4413, Tehran, Iran 2 Computational Physiology and Biology Laboratory, Department of Computer Engineering and Computer Science, California State University, Long Beach, CA 90840, USA 3 Material Science Research Laboratory, Department of Physics, S. V. College, Aligarh-202001, Uttar Pradesh, India 4 Bioengineering Research Group, Nanotechnology and Advanced Materials Department, Materials and Energy Research Center (MERC), P.O. Box 14155-4777, Tehran, Iran Received 24 November 2014; Accepted 8 December 2014; Available online 2 February 2015 Titanium is a typical biomaterial that is extensively used for fabrication of orthopedic and bone implants. Although it provides biocompatibility and osseointegration in major cases, in minor occasions the implant does not establish desired attachment with the surrounding bone tissue, which results in infection and failure. Recent studies demonstrate that electrochemical anodization of the bulk material can be employed as an effective technique to enhance biocompatibility of the titanium surface. In this paper, various aspects of such surface modification are reviewed to evaluate its potential for fabrication of next generation orthopedic implants.
Introduction In natural physiologic environment of the body, cells are supported by an extracellular matrix (ECM), which holds surface fluctuations in the range of nano-scale (1). Interestingly, synthetic surfaces have shown to provide improved cell interaction in presence of nanostructures on their surface as evidenced by promoted cell attachment, proliferation, differentiation (2-4) and mineralization (5). Although the bulk of implants can be engineered for bone substitution (6-8), surface modification is an alternative approach for fabricating a tissue replacement. Nanotechnology has revolutionized the ability of designing biomaterials and modifying their surface (9,10). Specifically, electrochemical anodization of titanium, which results in formation of titanium dioxide nanotubes on the surface of bulk titanium, has shown a great potential in improving biological characteristics of titanium. When titanium –and its alloys- are exposed to air, a native oxide layer with thickness of a few nanometers is formed on its surface. This oxide layer makes the material biocompatible. During electrochemical anodization process, titanium works as anode of an electrochemical cell and typically copper or graphite act
as cathode. Various types of electrolytes can be used as discussed in following sections. As power supply applies a constant voltage for specified duration, nanotubes gradually form on the surface of titanium (11). These nano-features mimic the natural bone structure in nanoscale and increase success of orthopedic implants. Variations in morphology of bone-implant interface influence potency of bone-implant contact. Nano-structured titanium dioxide, like other ceramics, enhances osteogenesis (12-14). Filopodia of the osteogenic bone cells enters nanotube pores and make interlocked bone implant interface. Following formation of nanotubes, surface area and surface energy is increased which -in part- enhance cell adhesion to the substrate. In addition, nanotubular surface provides nano-channels for delivery of nutrients to cells and removal of waste material from them (12). This can be considered as an aspect in which nanotubes mimic natural structure of bone. Flow of fluids plays and important role in physiologic environment (15-18) and presence of interstitial fluids is crucial during loading cycles on the bone tissue (19).
Cell response on anodized surface
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Coresponding author: M. Mozafari) E-mail:
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When a material is exposed to in vitro or in vivo condition,
Improving Cellular Response of Titanium Surface through Electrochemical Anodization
Figure 1: Presence of nanotubes on the surface of titanium supports adhesion of osteoblast cells to the material {Das, 2009 #24}. Reprinted with permission from Das et al. Copyright 2009 American Chemical Society
Figure 2: Scanning electron microscopy shows formation of highly ordered titanium dioxide nanotubes on the surface of titanium following anodization of the substrate {Marcin Pisarek, 2012 #66}. Reprinted from Pisarek et al.
proteins that are present in surrounding cell culture media or physiologic environment are quickly adsorbed to its surface (20). These proteins intermediate adhesion of cells to the substrate. Following adsorption of proteins, their functional groups (ligands) interact with cell receptors (integrins), which results in attachment of cells to the surface. Orthopedic implants mainly interact with two types of cells: (i) mesenchymal stem cells, which are potential to differentiate into osteoblasts and (ii) osteoblasts, which are bone building cells. Nano-features of substrate enhance differentiation of mesenchymal cells to osteoblasts and mineralization of osteoblasts (21,22). Secretion of extracellular matrix crucially affects cell viability. Synthesis and degradation of extracellular matrix dynamically occurs surrounding the cells (23). Presence of nanotubes on the surface of titanium enhances adhesion of osteoblast cells to the material compared with flat surface (figure 1).
Nanotubes with larger diameter promote desirable osteoblast behavior (33) and differentiation of mesenchymal stem cells (35). However, elsewhere it is reported that mesenchymal stem cells behave better on smaller nanotubes (36). These opposing reports may be due to application of inconsistent type of cell line, nano-features and experimental procedures. Results of an in vivo study indicate that the highest bone formation is observed on 70 nm nanotubes compared with 30 and 100 nm nanotubes (37). Effect of length of nanotubes on cellular attachment and differentiation is barely investigated and findings suggest that the length of nanotubes does not significantly affect cellular behavior (2).
Dimension of nanotubes Nanotubes that are formed during anodization are aligned in the same direction (perpendicular to the substrate) and have identical dimension (figure 2). Cellular behavior is influenced by change in dimension of titanium dioxide nanotubes. The location of integrins is dictated by spacing between nanotubes and the integrins location affects the force that is generated in the cells cytoskeleton. The tension is transduced to the cell nuclease (25). In this way, the force eventually determines the cell fate and its differentiation (26). Nano-features resemble ECM that transmits mechanical signals to chemical signals. Dimension of nanotubes can be controlled by application of specific variation in anodization conditions (14). It is known from literature that increasing anodization voltage leads to increase in diameter and length of nanotubes. Also increasing duration of anodization causes increase in length of nanotubes (27). Effect of nanotubes diameter is investigated typically in the range of 150 to 30 nm. Results show that decrease in diameter increases cellular attachment while contradictory results are reported for cell differentiation (28-32). It is shown that osteoblast cells (12,33) and mesenchymal stem cells (34) grown on nanotubes with diameter of 20 to100 nm behave differently.
Crystalline structure of nanotubes Heat treatment of anodized surface can further improve its biological properties. As-anodized nanotubes typically have amorphous structure. Heat treatment of the surface results in formation of crystalline structure depending on the heat treatment temperature. Following application of temperatures above 300 degree centigrade, the structure transforms into anatase crystalline and heat treatment above 450 degree centigrade results in rutile crystalline atomic order (39). Interestingly, cellular behave depends on the substrate atomic order. In general crystalline structures promote cellular behavior in comparison with amorphous structure. This behavior is attributed to removal of fluorine due to exposure to high temperatures (40) and decrease of water contact angle (41). Osteoblast cells show higher viability, mineralization and rate of proliferation on rutile-anatase mixture rather than amorphous substrate (40). However as-anodized titanium renders higher biocompatibility compared with non-anodizaed surfaces (33). In addition heat treatment increases mechanical stability of nanotubes on the substrate and prevents their detachment from the bulk material (42). Another advantage of crystalline nanotubes is higher resistance against corrosion (43).
Formation of nanotubes Titanium is widely used for fabrication of orthopedic implants due to its desirable mechanical and biological characteristics. From mechanical point of view, titanium provides high strength 87
N. Jalali, F . Moztarzadeh, A. Asgari, A. Zamanian, K.D. V erma, M. Mozafari
and low elastic modules. Biologically, the native oxide layer that is naturally formed on the surface of titanium makes it biocompatible. Generally titanium implants successfully bond with surrounding bone tissue without formation of fibrous tissue. However, in minor cases the implant is capsulated by a layer of connective tissue due to immune response of the body (44). Formation of fibrous tissue prevents strong osseointegration and eventually leads to loosening of implant and its failure (44). In order to minimize the failure rate of implants, various surface modifications have been performed. Recently, fabrication of nanotubes by anodization technique has shown great potential for production of next generation implants with improved surface biocompatibility (3,13,34,45). Various hypotheses have been rendered regarding the mechanism of formation of nanotubes. Under influence of electrical field titanium is dissolved in electrolyte and titanium oxide is deposited over the surface at the same time. Fluoride, as a typical component of anodization electrolyte, plays an important role in growth of nanotubes. In presence of fluoride both titanium and titanium oxide are chemically dissolved (46). During the initial stage of anodization, oxidation reaction is dominant compared with dissolution. As a result, thickness of the native oxide layer over the surface begins to increases. Since the oxide layer has less conductivity, the current that passes through the circuit is reduced sharply. During the next stage, dissolution of oxide layer results in formation of nano-pores that are evenly distributed over the surface. During the third stage, these nano-pores gradually transform into nanotubes. Since the surface area is increased by elongation of nanotubes, conductivity is slightly increased and more current passes through the anode. Finally, an equilibrium stage is achieved under which the rate of oxide dissolution at the top of nanotubes is equal to dissolution rate of titanium at the bottom. In this step, length of nanotubes remains constant and no more growth
is observed (figure 3) (47,48). Obtained nanotubes are perpendicular to the substrate and aligned in high order. In fact, the surface irregularities can be defined and controlled in higher precision compared with other methods of surface modification methods such as polishing, sand blasting and acid-etching. By controlling parameters such as anodization voltage, anodization duration, electrolyte components and relative ratio of electrolyte components, nanofeatures can be reproduced (49).
Surface hydrophilicity Surface hydrophilicity crucially affects biological properties of the material. As discussed in previous sections, proteins that are adsorbed on the surface, intermediate attachment of cells to the material (figure 4). Various parameters affect initial adhesion of proteins to the surface such as chemical and mechanical properties, energy, topography and hydrophilicity of the surface. It is shown that proteins have higher tendency to attach to hydrophilic surfaces rather than hydrophobic ones (50). Therefore, hydrophilic surfaces are more capable of promoting cell-substrate adhesion. Numerous studies show that water contact angle of titanium surface decreases following anodization (52,53). This observation can be explained by extension of surface area and increase of surface energy after formation of nanotubes. In addition, surface hydrophilicity of anodized surface is attributed to existence of OH– groups over the surface, arranged in Ti(OH) 4 structure. After exposure of anodized surface to air over a period of time, the hydroxyl groups are gradually removed from the surface to establish equilibrium for ongoing hydroxylation and dehydroxylation processes. Considering that titanium oxide stability is higher in form of TiO2 rather than Ti(OH)4, the present constituents follow this equation: Ti(OH)4 ! TiO2 + 2H2O (54). Subsequently, surface
Figure 3: Mechanism of formation of titanium dioxide nanotubes on the surface of titanium during electrochemical anodization {Rani, 2010 #119}. Reprinted with permission from Rani et al. Copyright 2010 American Chemical Society
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Improving Cellular Response of Titanium Surface through Electrochemical Anodization
have shown potential to be loaded with a wide range of drugs and antibiotics and deliver the loaded drug locally to the target tissue post-surgery. This capacity can be used to eventually fabricate drug-eluting implants that stimulate bone attachment and growth and prevent infection. It is demonstrated that functionalization of nanotubes with bone morphogenetic protein 2 (BMP2) enhances cellular proliferation and differentiation compared with non-functionalized surface (57). In similar a study, effect of coating nanotubes with epidermal growth factor is investigated. Results indicate that cells behavior is improved on the surfaces that were coated with epidermal growth factor (58). Also hydroxyapatite (59) and antibiotic (60) are successfully loaded inside nanotubes in order to stimulate mineralization and prevent bacterial growth respectively.
Figure 4: Proteins that are adsorbed on the surface, intermediate attachment of cells to the material {Brammer, 2012 #122}. Reprinted with permission from Jin et al. Copyright 2012 Elsevier Ltd.
hydrophilicity of anodized sample is gradually decreased over time. Hamlekhan et al. have shown that surface hydrophilicity can be controlled though optimizing fabrication conditions. Their results show that crystalline structure of the surface plays a key role in controlling establishment of surface equilibrium. Capability of preventing surface equilibrium is increased as heat treatment temperature is increased. In other words, the surface potency of maintaining its hydrophilicity follows this trend: rutile > anatase > amorphous (50,55,56).
Drug delivery Nanotubes are potential to be used as nano-carriers to deliver the drug locally (figure 5). In comparison with systemic drug delivery, local drug therapy renders some benefits. Local drug therapy enhances the efficiency of drug delivery to target tissue. In addition it prevents probable side effects caused by exposing other organs/tissues to the drug. Titanium dioxide nanotubes
Although nanotubes have shown great potential to act as nanocarriers, controlling drug release from nanotubes remains to be a challenge. Profile of drug release over time typically shows a sudden release at the initial stage of release followed by sustained release of drug during the next stage. It is desirable to prevent the sudden release of drug during the first stage and achieve a sustained release over a long period of time. Numerous studies have been performed to prevent the burst release of drug and they have been successful in prolonging drug release to about 1 month (62-64). Various methods have been investigated to prolong drug release. Dimension of nanotubes can be adjusted to control rate of drug release (63). Many methods apply polymers either in form of coating or nano-particles to prevent the burst release. In form of coating, multiple layers of gelatin and chitosan have successfully prevented sudden release of BMP2 from nanotubes (65). In form of nano-particles, the drug is typically incorporated into polymeric micelles and then the drug-loaded micelles are loaded into nanotubes.
Summary and conclusion Fabrication of titanium dioxide nanotubes on the surface of titanium implants as a surface modification method has shown various benefits. It directs differentiation of mesenchymal stem
Figure 5: TEM images suggest that drug can be intercalated in nanotubes either in (a) amorphous or (b) crystalline structure (61). Reprinted with permission from Shokuhfar et al. Copyright 2013 American Chemical Society
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cells to bone forming cells, osteoblasts. In addition, nanotubes enhance adhesion of osteoblasts to the surface, their proliferation, differentiation and mineralization. Nanotubes can be reproduced in precise dimension by controlling anodization condition. Biological characteristics of nanotube-coated surface are further improved following heat-treatment. Also nanotube have shown potential in delivering the drug locally to target tissue. Considering these advantages, nanotubes are strong candidate for fabrication of next-generation implants that are able to deliver drug locally. Further in vivo studies will be valuable to shed light on capability of nanotubes.
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