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Original article
11 (
7
); 1126-1133
doi:
10.1016/j.arabjc.2015.02.010

Surface modifications of titanium implants by coating with bioactive and biocompatible poly (ε-caprolactone)/SiO2 hybrids synthesized via sol–gel

, ,
 Department of Industrial and Information Engineering, Second University of Naples, Via Roma 21, 81031 Aversa, Italy

⁎Corresponding author. Tel.: +39 0815010360; fax: +39 0815010204. michelina.catauro@unina2.it (Michelina Catauro)

Received: , Accepted: ,
© The Author(s) 2015
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Class I organic/inorganic hybrid materials have been synthesized by sol–gel method from a multicomponent solution containing tetraethyl orthosilicate (TEOS), water, ethanol and nitric acid by adding different percentages of poly (ε-caprolactone) (PCL) dissolved in chloroform. Those hybrids have been used, in sol phase, to dip coat commercially pure titanium (CP Ti) grade 4 substrates with the aim of transferring to them the known biological properties of silica-based sol–gel materials. Particular attention has been directed to investigate the effect of PCL amount on both structure and coating performances.

The chemical composition of the films was ascertained by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) analysis. Scanning electron microscope (SEM) proved that polymer allows to make crack-free coatings.

The biological performances of the un-coated and coated substrates were compared and evaluated by means of bioactivity test and WST-8 assay. SEM and energy dispersive X-ray (EDX) analyses have detected higher hydroxyapatite nucleation on the surface of the coated substrates after soaking in a fluid simulating the composition of the human blood plasma (SBF). Moreover, higher vitality of NIH 3T3 mouse embryonic fibroblast cells seeded on coated specimens was recorded. The results, thus, prove that coating application effectively improves the bioactivity and biocompatibility of CP Ti grade 4 substrates.

Keywords

Sol–gel
Organic/inorganic hybrid
Dip coating
Bioactivity
Cell viability
1

1 Introduction

The sol–gel process is a versatile synthesis method used to produce glasses and ceramics at low temperatures. Sol–gel chemistry is based on the hydrolysis and polycondensation of metal alkoxides (M(OR)n, where M = Si, Sn, Ti, Al, Mo, V, W, Ce and so forth). The following sequence of reactivity is usually found: Si(OR)4 << Sn(OR)4 = Ti(OR)4 < Zr(OR)4 = Ce(OR)4 (Novak, 1993; Brinker and Scherer, 1989). As silicon alkoxides are not very reactive, sol–gel process is slow and easy to control in order to produce a transparent gel.

Sol–gel reactions are known to be affected by many parameters of the synthesis procedure, such as the structure and the concentration of the reactants, solvents and catalysts, as well as the reaction temperature and the rate of removal of by-products and solvents (Brinker and Scherer, 1989; Klein, 1988). The process occurs at low temperatures, therefore it is possible to add thermolabile substances, such as polymers and/or drug, to the glassy matrix. It was observed that under acid catalysis and carefully controlled conditions, it is possible to obtain transparent and monolithic hybrid/composite materials (Sanchez and Ribot, 1994).

At first glance, those materials are considered as biphasic materials, where the organic and inorganic phases are mixed at nanometer and sub-micrometer scales. Nevertheless, their properties are not just the sum of the individual contributions from both phases; the role of the inner interfaces can be predominant. The nature of the interface has been used by Judeinstein et al. to divide those materials into two distinct classes (Judeinstein and Sanchez, 1996). In class I, organic and inorganic compounds are embedded and only weak bonds (hydrogen, van der Waals or ionic bonds) allow the cohesion to the whole structure. In class II materials, the phases are linked together through strong chemical bond (covalent or ionic-covalent bonds).

There is a considerable interest in organic–inorganic hybrid/composite materials prepared via the sol–gel process. A variety of organic polymers have been introduced into inorganic networks to obtain hybrid or composite materials, with or without covalent bonds between the components, to be used in several applications (Aronne et al., 2012; Catauro et al., 2015b; Ferreira-Neto et al., 2013; Catauro and Bollino, 2014; Poologasundarampillai et al., 2010). The attention of the present work is directed to their use in the biomedical field. Materials prepared by sol–gel process, in fact, have shown to be more bioactive than those with the same composition but prepared with different methods. That is due to the presence of hydroxyl groups on their surface which can promote the nucleation of calcium and phosphate and, thus, the osseointegration after implantation (Gupta and Kumar, 2008; Catauro et al., 2014b,e,h). That property, together with the opportunity to introduce drugs and/or biocompatible polymers to improve the mechanical properties of the glassy network has enabled to develop glasses, ceramics and hybrids which can be used as support matrices for the controlled release of drugs and/or implantable therapeutic systems, filling materials for bone or tooth repair (Premnath et al., 2014; Catauro et al., 2014a; Flanagan et al., 2010; Catauro et al., 2010). Moreover, the possibility to combine sol–gel methods with a range of coating techniques, e.g. dip, spin and spray coating, makes it an ideal technology for the production of bioactive and biocompatible coatings (Catauro et al., 2014a,f, 2015a; Hernandez-Escolano et al., 2012). Dip coating technique was used in many works to apply a material on substrates with complex shapes and, thus, to modify the properties related to their surface retaining the good properties of the bulk. That process requires the object to be dipped into the ‘sol’ and withdrawn at a constant speed to enable the sol drainage and its instantaneous gelation. The withdrawal speed is a very important parameter, as it influences the thickness and the morphology of the coating layer (Brinker and Scherer, 1989; Klein, 1988).

In this work a sol–gel dip coating route was optimized to synthesize SiO2/PCL hybrid material nanocomposites and use them to modify the surface properties of commercially pure titanium (CP Ti) grade 4 implants to improve their bioactivity and biocompatibility. It is known, in fact, that SiO2 glasses are bioactive (i.e. they are able to bond to living bone (Kokubo, 1991)) and in vivo biocompatible (Wilson et al., 1981; Palumbo et al., 1997; Catauro et al., 2014a,d). The two main applications of silica-based materials in medicine and biotechnology are for bone-repairing devices and for drug delivery systems (Vallet-Regi and Balas, 2008). However, as they have poor mechanical properties, monolithic glasses cannot be used in load-bearing applications, where metallic alloys are still the materials of choice. For this reason, their use as coatings of metal implants was explored in order to obtain a material with the biological properties of the silica-based glasses and mechanical properties of the metallic alloys.

Many works report the introduction of organic components into the inorganic sol–gel to form organic/inorganic hybrid sol–gel coatings to reduce their intrinsic brittleness (Kangasniemi et al., 1994). For this purpose, the Authors added the poly (ɛ-caprolactone) (PCL), a biocompatible aliphatic polyester which has been shown to act as plasticizer giving elasticity and enabling to obtain crack-free coatings with good adhesion properties (Catauro et al., 2014c,g). Although, several types of the SiO2/PCL hybrid gels have been so far investigated (Lee et al., 2010; Rhee et al., 2002; Shin et al., 2011) and there has been little research on their use as a coating material for bone tissue engineering. The results obtained showed that the use of hybrid coatings, consisting of silica and PCL to modify the surface of CP Ti grade 4 substrates allowed to prepare implants for dental and orthopedic applications which could have high ability of in vivo osseointegration.

2

2 Materials and methods

2.1

2.1 Sample preparation

Organic–inorganic hybrid materials were prepared by means of sol–gel process from analytical reagent grade tetraethyl orthosilicate (TEOS, Sigma Aldrich) and poly (ɛ-caprolactone) (PCL Mw = 14,000, Sigma Aldrich). Fig. 1 shows the flow chart of the hybrid synthesis. To prepare the inorganic sol, the metal alkoxide precursor (TEOS) was added to a water–alcohol (99.8%, Sigma Aldrich) solution, containing nitric acid (65 wt%, Sigma Aldrich) as catalyst, using molar ratio TEOS:HNO3:EtOH:H2O = 1:1:7.5:1. To synthesize SiO2/PCL hybrid materials, solutions of PCL in chloroform (Sigma Aldrich) were added to the inorganic sol and, thus, five hybrid systems entrapping different percentages of the polymer (0, 5, 10, 20 and 30 wt%) were obtained. CP Ti grade 4 disks of 8 mm diameter (Sweden & Martina, Padua, Italy), previously cleaned and then passivated in a solution of HNO3 65 wt% (to form an anti-corrosive TiO2 layer) were dipped into the synthesized sols (see Fig. 1) by means of a KSV LM dip-coater (KSV instruments Ltd, Finland). The substrates were provided with a pin to be attached to the clip of the dipper module of the instrument (as shown in Fig. 2) and to allow their upward movement at a constant speed. The coatings were prepared by setting the withdrawn speed to 20 mm/min and by heat-treating the coated substrates in an oven at 45 °C for 24 h to promote the film densification without any polymer degradation. Also the wet gels obtained after the gelation of the sols (6–10 days after the synthesis, depending on PCL amount) were heat-treated in the same way and a monolithic glass was obtained as shown in Fig. 3.

Flow chart of SiO2/PCL gel synthesis and dip coating procedure.
Figure 1
Flow chart of SiO2/PCL gel synthesis and dip coating procedure.
CP Ti grade 4 substrate attached to the dipper module of the instrument.
Figure 2
CP Ti grade 4 substrate attached to the dipper module of the instrument.
SiO2/PCL gel after drying.
Figure 3
SiO2/PCL gel after drying.

2.2

2.2 Coatings characterization

The morphology of the obtained coatings has been studied by a scanning electron microscope (SEM) Quanta 200 FEI (Europe Company, Netherlands).

To analyze the chemical composition of the obtained coatings, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra were recorded on a Prestige-21 FTIR spectrometer equipped with an AIM-8800 infrared microscope (Shimazu, Japan), using the incorporated 3-mm diameter Ge ATR semicircular prism. The spectra were recorded using a 30° angle of incidence for a total of 64 scans at a resolution of 4 cm−1 and in the 650–4000 cm−1. The spectra were elaborated by Prestige software (IRsolution).

2.3

2.3 Coatings biological properties

In order to study their bioactivity, CP Ti grade 4 disks, both uncoated and coated with the synthesized hybrid materials, were soaked in a simulated body fluid (SBF) with an ion concentration nearly equal to that of the human blood plasma, as reported elsewhere (Kokubo and Takadama, 2006). During soaking the temperature was kept fixed at 37 °C. Taking into account that the ratio of the exposed surface to the volume solution influences the reaction, 10 mm2 per ml of solution was used (Kokubo and Takadama, 2006).

The ability of the coatings to promote the nucleation of an apatite layer on their surface was evaluated after 7, 14 and 21 days of exposure to SBF by submitting reacted samples to SEM analysis using the microscope FEI Quanta 200 equipped with energy dispersive X-ray (EDX). SEM was used to detect the typical globular crystals of hydroxyapatite, as reported by (Kokubo and Takadama, 2006), and EDX to carry out their microanalysis to confirm globules identity.

To evaluate the coatings biocompatibility NIH 3T3 murine fibroblasts (ATCC, VA, USA) were seeded on the CP Ti grade 4 coated substrates and cells viability was tested with WST-8 Assay (Dojindo Molecular Technologies Inc., MD, USA).

Cells were maintained in DMEM medium (Gibco, CA, USA) with 10% (v/v) fetal bovine serum, 1% pen-strep, in a humidified incubator, at 37 °C, 5% CO2 and 95% air.

CP Ti grade 4 disks were placed on the bottom of a 24-well plate, using three coated disks for each system (0, 5, 10, 20 and 30 wt% of PCL) and three uncoated disks for the negative control. The vitality of the cells grown on the well bottom has represented 100% viability. Each point was done in triplicate.

NIH 3T3 cells were amplified in a 25 cm2 flask, and detached at semi-confluence using trypsin–EDTA (Gibco) composed of 2.5% w/v of trypsin and 0.2% w/v EDTA in phosphate buffered saline (PBS). 5000 cells, counted by means of a Burker chamber, were seeded on CP Ti grade 4 coated and un-coated disks as well as on the well bottom; they were washed 3 times with PBS after 24 h of incubation and were again incubated with 10% v/v of WST-8 in a fresh medium (50 ml in 500 ml of culture medium) for 2 h.

The tetrazolium salt of WST-8 [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt] was used as a metabolism indicator, as that salt penetrates into the viable cells, where it is metabolized by the mitochondrial dehydrogenases. Those enzymes convert the tetrazolium salt, water-soluble and of purple color, in yellow-orange crystals of formazan. The amount of formazan is evaluated by recording the absorbance at 450 nm using an UV–visible spectrophotometer (Biomate 3, Thermo Scientific). Formazan concentration and, thus, the absorbance value was directly proportional to the number of viable cells.

Statistical analyses of the obtained results were performed using the Student’s t test.

3

3 Results and discussion

3.1

3.1 Chemical characterization

The detailed chemical and microstructural characterization of the hybrids SiO2/PCL was carried out by Catauro et al. elsewhere (Catauro et al., 2013) by means of several instrumental techniques. FTIR and solid state NMR showed that the organic and inorganic phases interact through the formation of hydrogen bonds between the carbonyl groups of the polymer chains (H-bond acceptor) and the hydroxyl group of the inorganic matrix (H-bond donator), proving that the obtained materials can be classified as class I hybrids, according to Judenstein and Sanchez classification (Judeinstein and Sanchez, 1996). Moreover, X-ray diffraction (XRD) analysis did not detect sharp peaks visible in PCL diffractogram and typical of crystalline phases, SEM micrographs did not evidence the presence of different phases while atomic force microscope (AFM) topographies have shown that the average domains are less than 400 nm in size (Wei et al., 1998), confirming that the synthesized materials are completely amorphous homogenous organic–inorganic hybrids nanocomposites.

Those materials were used in the present work to obtain transparent and homogeneous coatings, as shown in Fig. 4, where SEM micrographs of all coatings, either as wholly inorganic or as hybrids, are reported. Although thin coatings facilitate the gas removal (including alcohol) and the formation of small thermal gradients within the layer, the coating of SiO2 appears to be fractured (Fig. 4A). The cracks formation decreased when polymer was added to the silica matrix and crack-free films were obtained using high PCL amounts (20 and 30 wt%) (Fig. 4C and D). Authors proved elsewhere that the reduction of coating fractures when the PCL is present is ascribable to an increase of the coating elasticity (Catauro et al., 2014c,g).

SEM micrograph of (A) SiO2 (B) SiO2 + PCL 5 wt% (C) SiO2 + PCL 10 wt% (D) SiO2 + PCL 20 wt% and (E) SiO2 + PCL 30 wt% coatings.
Figure 4
SEM micrograph of (A) SiO2 (B) SiO2 + PCL 5 wt% (C) SiO2 + PCL 10 wt% (D) SiO2 + PCL 20 wt% and (E) SiO2 + PCL 30 wt% coatings.

The presence of both phases (PCL and SiO2) in the coatings was investigated by means of ATR-FTIR spectroscopy and the recorded spectra are reported in Fig. 5. Curve a is the ATR-FTIR spectrum of the inorganic silica coating. All typical peaks of SiO2 sol–gel materials are visible, such as the bands at 1065 (with a shoulder at 1200 cm−1) and 790 cm−1 due to asymmetric and symmetric Si—O stretching vibrations in the SiO4 tetrahedra. Moreover, the band at 950 cm−1, typical of alkoxy-derived silica gels, assigned to Si—OH bonds vibrations (Yoshino et al., 1990; Piccirillo et al., 2012), and a peak at 1640 cm−1, due to —OH bending vibrations in the water, are present.

ATR-FTIR spectra of (a) SiO2 (b) SiO2 + PCL 5 wt% (c) SiO2 + PCL 10 wt% (d) SiO2 + PCL 20 wt% (e) SiO2 + PCL 30 wt% coatings and (f) pure PCL.
Figure 5
ATR-FTIR spectra of (a) SiO2 (b) SiO2 + PCL 5 wt% (c) SiO2 + PCL 10 wt% (d) SiO2 + PCL 20 wt% (e) SiO2 + PCL 30 wt% coatings and (f) pure PCL.

In the ATR-FTIR spectra of the SiO2/PCL coatings (Fig. 5 from curve b to e), all described peaks are still visible and furthermore some signals ascribed to PCL (Krzaczkowska et al., 2005; Chellamani et al., 2013) (spectrum reported in Fig. 5f) appear and their intensity increases in the spectra of the hybrid systems containing higher amounts of polymer (curve from c to e). In particular, the bands at 2933 and 2864 cm−1, due to CH2 asymmetric and symmetric stretching of PCL respectively, appear together to the typical C⚌O peak which generally is visible at 1732 cm−1 and in the hybrid spectrum appears at 1710 cm−1. The shift of that peak to lower wave numbers suggests the formation of H-bonds between the polymer and the inorganic matrix. The hypothesis is supported by literature. Many works describe the ability of the sol–gel inorganic matrix to use their —OH groups to form H-bonds with polymers, which have functional groups able to acts as H-bond acceptor(Catauro and Bollino, 2014; Catauro et al., 2013; Catauro and Bollino, 2013; Catauro et al., 2010; Piccirillo et al., 2011). Also the chemical characterization of the monolithic SiO2/PCL hybrid carried out by the Authors elsewhere (Catauro and Bollino, 2013) supports this interpretation. Moreover, in SiO2 + 30%PCL spectrum (curve e) also the peak at 1455 cm−1, due to methylene C—H bending, and the peaks at 1280 cm−1, ascribed to O—C stretching, appear as weak signals.

3.2

3.2 Coating biological properties

It is reported in literature that SiO2-based sol–gel materials are highly bioactive and biocompatible (Catauro and Bollino, 2013, 2014; Catauro et al., 2014a; Palumbo et al., 1997; Wilson et al., 1981) due to the exposed —OH groups on the surface which promote hydroxyapatite nucleation by attracting the Ca2+ ions present in the SBF. The increase of the positive charge on the surface induces the Ca2+ ions to combine with the negative charge of the PO42− ions to form an amorphous phosphate, which spontaneously transforms into hydroxyl-apatite [Ca10(PO4)6(OH)2] (Hayakawa et al., 1999; Ohtsuki et al., 1992).

In order to evaluate if the biological properties of those materials were transferred to the coated substrates, both the uncoated and coated CP Ti grade 4 disks were subjected to biological tests.

They were soaked in SBF for “in vitro” bioactivity test. SEM micrographs after different exposure times (7, 14 and 21 days) evidence that on the sample surfaces the formation of the typical globules, described by (Kokubo and Takadama, 2006), already occurs after 7 days (Fig. 6B). By comparing SEM images of an uncoated substrate (Fig. 6A) with a coated one (Fig. 6B), it is possible to note that fewer globules are visible on the surface of the uncoated sample.

SEM micrograph of (A) uncoated and (B) SiO2/PCL coated CP Ti grade 4 samples after 7 days of soaking to SBF; (C) SiO2/PCL coated CP Ti grade 4 sample after 21 days of soaking to SBF; (D) EDX analysis of globules (area in the ring).
Figure 6
SEM micrograph of (A) uncoated and (B) SiO2/PCL coated CP Ti grade 4 samples after 7 days of soaking to SBF; (C) SiO2/PCL coated CP Ti grade 4 sample after 21 days of soaking to SBF; (D) EDX analysis of globules (area in the ring).

After 21 days (Fig. 6C) the whole surface of all coated samples is covered by a globular precipitate. Its typical shape and EDX analyses (Fig. 6D) allowed to identify it as hydroxyapatite because the ratio between the atomic contents of Ca and P is 1.6 in agreement with the chemical formulation of that mineral (Kokubo and Takadama, 2006; Ohtsuki et al., 1992).

Moreover, SEM images show that the distribution of the hydroxyapatite grains is similar for all the samples and, therefore, only representative SEM micrographs are reported in Fig. 6.

The nucleation process on CP Ti grade 4 disks, thus, is promoted by the presence of the coating but it is not significantly influenced by PCL content.

WST-8 assay shows that the viability of NIH 3T3 cells in contact with the coatings was improved in comparison with that of cells grown on CP Ti grade 4 uncoated samples. The highest values of cell viability were obtained using coatings of SiO2 and SiO2 + PCL 6 wt%, whereas the coatings containing higher polymer amount cause a slight decrease of viability (see Fig. 7). Therefore, the results prove that the coatings presence improves the biocompatibility of the CP Ti grade 4, especially if low amount of PCL are contained. This is in agreement with other works in literature where the effect of slight inhibition caused by high amount of PCL is reported (Catauro et al., 2014a; Allo et al., 2012). That effect is caused by the hydrophobic nature of PCL which inhibits cells adhesion and consequently a decrease of cells vitality. On the other hand, the study of the contact angle carried out on PCL coating (Teng et al., 2014) showed that the addition of SiO2 to the PCL films leads to an increase of coating hydrophilicity which can explain why the negative influence of PCL is observed only for high polymer amount.

WST-8 assay results: vitality of NIH 3T3 cells seeded on SiO2, SiO2/PEG coatings and uncoated titanium (Ti-4); cells grown on polystyrene were considered 100% of viability.
Figure 7
WST-8 assay results: vitality of NIH 3T3 cells seeded on SiO2, SiO2/PEG coatings and uncoated titanium (Ti-4); cells grown on polystyrene were considered 100% of viability.

4

4 Conclusions

Sol–gel technique enabled to synthesize organic–inorganic hybrid systems consisting of a silica matrix in which different weight percentages of PCL were entrapped. The used dip-coating procedure allowed to obtain thin and homogeneous films on CP Ti grade 4 disks. Moreover, the presence of PCL improved the coating elasticity achieving a crack-free coatings production.

The evaluation of the biological properties of the obtained coatings showed an improvement of the CP Ti grade 4 performances. Indeed, the SiO2/PCL coated substrates appear more bioactive and less cytotoxic than those uncoated. The main contribution to such biological performances is provided by the inorganic component, as proved by the viability of the NIH 3T3 cells seeded on SiO2 coated substrates. However, PCL addition is essential for obtaining crack-free coating.

In conclusion, the obtained results suggest that hybrid coatings can be used to modify the surface of titanium implants to improve their osseointegration process after implantation.

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