Hybrid Coatings of Chitosan-Tetracycline-Oxide Layer on Anodized Ti-13Zr-13Nb Alloy as New Drug Delivery System

Comparison with the osteoconductivity and bone-bonding ability of the iodine supported titanium, titanium with porous oxide layer and the titanium alloy in the rabbit model.

TiO2 nanotubes formed by anodization in fluoride-containing electrolytes have been extensively examined due to their wide rage of applications. It is reported that fluoride ions move faster to the interface between anodic oxide layer and underlying Ti substrate, forming a fluoride-rich layer at the interface as the ionic radius of fluoride ion is smaller compared to that of oxygen ion. The fluoride-rich layer is also reported to decrease the adhesion of the anodic oxide layer to the substrate. Therefore, the formation of nanotubular oxide layer in fluoride-free electrolytes is highly desired. In the present work, we examined the formation of nanotubular oxide layers on pure Ti in highly concentrated sulfuric acids. Specimens with the dimension of 5 mm x 80 mm x 0.6 mm were prepared from pure Ti sheet (purity ; 99.5%). Prior to anodization, the specimens were cleaned in acetone, methanol and deionized water, successively. Anodization was carried out in highly concentrated sulfuric acids at elevated temperatures using two-electrode configuration cell with platinum counter electrode. The applied voltage was increased with the sweep rate of 1 V/s to desired voltages and then kept at the voltages for various durations. After the anodization, the surface of the specimens was cleaned with deionized water and dried. The structure of the surface was evaluated using FE-SEM. In a highly concentrated sulfuric acid, the anodic current increased with increasing the applied voltage and after switching constant voltage, decreased with time. The formation of oxide layer was confirmed at the surface, but no porous structure was visible. However, a porous structure was observed on the specimen above the electrolyte surface, indicating that the anodization occurred under the meniscus consisting of highly concentrated sulfuric acids. The optimization of water concentration in sulfuric acid and temperature led to the formation of porous structure on pure Ti. This indicates that porous oxide layers can be formed in fluoride-free electrolytes although further optimization is required to improve the ordering of pores.

The formation of microporous oxide layers on titanium (Ti) by anodization in sulfuric acid (H2SO4) solution and the influence of prior hydrogen charging on their properties are examined using electrochemical techniques, scanning electron microscopy, grazing incident X-ray diffraction, and X-ray photoelectron spectroscopy. When Ti is anodized in 1 M aqueous H2SO4 solution at a high direct current (DC) potential (>150 V) for 1 min, a porous surface layer develops, and the process takes place with spark-discharge. Under these conditions, oxygen evolution at the Ti electrode proceeds vigorously and concurrently with the formation of anodic oxide. The oxygen gas layer adjacent to the Ti surface acts as an insulator and triggers spark-discharge; the latter stimulates the development of pores. In the absence of spark-discharge, the oxide layer has extended surface roughness but low porosity. A porous oxide layer can be prepared by applying a lower DC voltage (130 V) and without spark-discharge, but Ti requires prior hydrogen charging by cathodic polarization in 1 M aqueous H2SO4 solution. Mott-Schottky measurements indicate that the oxide layers are n-type semiconductors and that the charge carrier density in the anodic oxide layer on the hydrogen-charged Ti is lower than in the case of untreated Ti. The hydrogen charging also affects the flat band potential of the anodic oxide layers on Ti by increasing its value. The reduced charge carrier density brought about by hydrogen charging decreases the oxide layer conductivity and creates favorable conditions for its electrical breakdown that stimulates the development of pores. The porous layer on the hydrogen-charged Ti consists of anatase and rutile phases of TiO2; it has the same chemical composition as the porous layer obtained on untreated Ti. X-ray photoelectron spectroscopy measurements show that prior hydrogen charging does not affect the thickness of anodic oxides on Ti. The porous oxide layer on Ti enables the growth of hydroxyapatite, thus revealing good bioactivity in simulated body fluids.

Sustained release of pharmaceutical drug has been a challenge to medical practitioners for a very long time. This is a requirement of anaesthetists, endoscopic surgeons and even dentists. Though commercial bandages are already available for pain and inflammation control, their drug release mechanism is mostly unknown, and is predominantly erratic. This poses a dilemma for medical practitioners, due to which, even if it is recommended to keep patch adhered to skin for 6 hours, it is often replaced in couple of hours or many a times a good amount of undelivered drug remains in the patch and gets wasted. Combining this need for systematic release of drug through such commercial patches and the property of sustained release of drug molecules through mesoporous silica particles, led to an idea for using a coat of Silica Microparticles (SiMPs) on to these patches to achieve controlled and sustained release of drug, mainly Ketoprofen (KP) (a pain-relieving commercial drug). SiMPs were synthesised and coated with pure KP drug on one hand and on another a thin layer of SiMPs was coated on the commercial KP patch. The sustained release studies were done for duration of 6-8 hours. The structural chemistry and the interaction chemistry of the silica-trapped-KP showed that the carboxylic acidic group of hydrogen from KP makes partial bond with silica through weak van-der-Waal forces interaction and efficiency of 75 % of drug loading. The commercial KP patch showed initial burst and later erratic release. However, KP patches upon coating with SiMPs showed controlled release of drug, with the initial burst release and subsequent sustained release in the agar platform-based drug release study. Loose conjugational chemistry, with good bio-availability of SiMPs provides a fine control over the release mechanism, which probably forms a fine mesh-matrix through which the drug slowly percolates. Further, since the particles are not too small, the passage of these particles through the skin-barrier is also less-probable, thereby imparting a facilitative effect for drug passage, in a controlled fashion. Hence a simple strategy is proposed to achieve better medicinal patches for pain-control and better drug efficacy.

＜Introduction＞ Titanium (Ti) and Ti alloys are widely used in both field of orthopedics and dentistry because of their good mechanical properties, high corrosion resistance, and biocompatibility. However, in recent years, biofilm formation due to bacterial adhesion and colonization on biomaterials has been recognized as a major cause of failure in implant surgeries. There is no way to remain devices coated by biofilm in the patient body, because the resultant infection disease will occur. To solve a problem of biofilm formation on biomaterials surface, application of antibacterial agents is the first choice. Silver (Ag) ion is known as one of the most effective antibacterial agents. Therefore, the surface treatment which enables to modify the implants to incorporate Ag should be developed for realizing antibacterial property. We focus on the micro-arc oxidation (MAO) treatment which has been already applied to medical devices consisting of Ti because of its efficacy on improvement of hard-tissue compatibility. The MAO treatment was also expected to be available for Ag-introducing method onto Ti surface. Thus, in this study, MAO treatment with the Ag-containing electrolyte was performed. The purpose of this work was to control and optimize the Ag ion release from the modified layer by MAO treatment condition. Surface analyses were performed to characterize the composition, morphology, and crystal structure of the MAO-treated Ti, followed by a bacterial adhesion test. <Materials and Methods> Commercially pure Ti (Grade 2) disks were ground by SiC abrasive papers up to #800 grit. The composition of the electrolyte for MAO treatment was 100-mM calcium glycerophosphate, 150-mM calcium acetate, and 0 to 2.5-mM silver nitrate (AgNO3). After pouring the electrolyte into the electrochemical cell, a Ti specimen as anode and a stainless steel plate as cathode were connected to a DC power supply (PL-650-0.1, Matsusada Precision Inc., Japan). A positive voltage, with the adjustment of the constant current density condition of 251 Am-2 was applied for 10 min. After MAO treatment, Ti specimens were rinsed in ultra-pure water for 3 min. The surface morphologies and the chemical compositions of the specimens were analyzed using a scanning electron microscope with energy dispersive X-ray spectrometer (SEM/EDS, S-3400NX, Hitachi High-Technologies Corp., Japan). The Ag-ion release from the MAO-treated specimens into a physiological saline (0.9mass% NaCl aq.) was measured by an inductively coupled plasma atomic spectrometer (ICP-AES, ICPS-7000 ver.2, Shimadzu Corp., Japan). The saline had been exchanged for the fresh one every 7 d. To evaluate the antibacterial property of the MAO-treated specimen, the bacterial adhesion test was performed with anaerobic gram-negative bacterium (Escherichia coli, NBRC3972, NITE, Japan) in accordance with the standard test method (ISO22196:2011). The bacteria were seeded on the specimen surface and then incubated at 35 °C for 24 h. The colony forming units (CFU) mL-1 of the living bacteria dispersed into the saline was measured using the culture medium sheet for E. coli (JNC Corp., Japan). ＜Results and Disccution＞ The MAO-treated specimens in the electrolyte containing Ag showed a typical structure of porous oxide layer as reported in previous studies. Thus, it is supposed that the presence of Ag ions in the electrolyte does not influence the formation of the porous oxide layer during MAO treatment. The incorporations of Ag as well as Ca and P from the electrolyte in the oxide layer during MAO treatment were confirmed by EDS analysis. From the results of ICP-AES measurement, the release rate of Ag ion from the oxide layer into a physiological saline was unstable until 21 d after the immersion. However, the Ag ion release was stabilized after 28 d and it had kept for at least 140 d. The specimens treated in the above 0.5-mM AgNO3 showed no viable bacterium on their surface even after the immersion in a physiological saline for 28 d. Thus, it was confirmed that the incorporated Ag in the porous oxide layer by MAO was effective against bacterial adhesion. In addition, we also found that the more Ag was incorporated when the potential reached higher value. According to the above results, we have finally developed the two-step MAO treatments which can control the Ag-ion release during immersion in a physiological saline by altering the electrolyte composition or the maximum voltage setting in the middle period of the treatment.

Polymer-based hydrogels are hydrophilic polymer networks with crosslinks widely applied for drug delivery applications because of their ability to hold large amounts of water and biological fluids and control drug release based on their unique physicochemical properties and biocompatibility. Current trends in the development of hydrogel drug delivery systems involve the release of drugs in response to specific triggers such as pH, temperature, or enzymes for targeted drug delivery and to reduce the potential for systemic toxicity. In addition, developing injectable hydrogel formulations that are easily used and sustain drug release during this extended time is a growing interest. Another emerging trend in hydrogel drug delivery is the synthesis of nano hydrogels and other functional substances for improving targeted drug loading and release efficacy. Following these development trends, advanced hydrogels possessing mechanically improved properties, controlled release rates, and biocompatibility is developing as a focus of the field. More complex drug delivery systems such as multi-drug delivery and combination therapies will be developed based on these advancements. In addition, polymer-based hydrogels are gaining increasing attention in personalized medicine because of their ability to be tailored to a specific patient, for example, drug release rates, drug combinations, target-specific drug delivery, improvement of disease treatment effectiveness, and healthcare cost reduction. Overall, hydrogel application is advancing rapidly, towards more efficient and effective drug delivery systems in the future.

Self-organized high aspect ratio porous hafnium oxide prepared by electrochemical anodization

tert-Butylamine functionalized MCM-41 mesoporous nanoparticles as drug carriers for the controlled release of cyclophosphamide anticancer drug

Introduction:Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body.Areas covered:Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations.Expert opinion:Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients.

Investigation of the drug distribution and release characteristics from particulate membranes

Surface characteristics and osteoblast cell functions were investigated for the nano-structured oxide layer on commercially pure titanium (CP-Ti) fabricated using microarc oxidation (MAO) and hydrothermal treatment (HT) methods. Ti-MAO-135HT, Ti-MAO-150HT, and Ti-MAO-175HT groups were fabricated by hydrothermally treating the MAO-treated specimens (Ti-MAO) in phosphorus-containing alkaline solution at temperatures of 135, 150, or 175 °C, respectively. After hydrothermal treatment, a nanosheet-shaped morphology, nano-needles and nanorods were observed on the porous surface of the Ti-MAO-135HT, Ti-MAO-150HT and Ti-MAO-175HT groups, respectively. The roughness was not significantly different for all groups. However the contact angle decreased dramatically as the hydrothermal temperature increased. The osteoblastic cell adhesion and viability of the Ti-MAO-150HT and Ti-MAO-175HT groups were significantly lower compared to those of the Ti-MAO group. This study showed that nano-topology formed on micro porous oxide layer was more important than hydrophilicity in its effect upon initial osteoblastic cell functions.

Formation and characterization of anodized layers on CP Ti and Ti-6Al-4V biomaterials

Halloysite nanotubes (HNTs) are fascinating carriers for the delivery of chemotherapy drugs. Surface modification of HNTs and their loading in polymer matrixes can create a delivery system with more controlled and sustained drug release. Taking this into account, in the present research, a drug delivery system was made by grafting a block copolymer of polyacrylic acid (PAA)/polyaniline (PANI) on HNT surface and incorporating copolymer-grafted HNTs into the polycaprolactone (PCL) fibers. For this purpose, PANI-b-PAA copolymer was first formed on HNT surface by grafting from strategy. Then, the copolymer-grafted HNTs and doxorubicin were loaded into PCL solution and the composite solution was processed by electrospinning. Preliminary evaluations confirmed the successful grafting of PANI-b-PAA copolymer onto HNTs. SEM and EDS analyses showed that drug loaded composite nanofibers have an average diameter of 396 nm and a uniform distribution of HNTs and doxorubicin. Drug release study revealed that composite nanofibers have less burst release and more sustained release than PCL nanofibers. Investigation of drug release mechanism by kinetics models corroborated that the drug release from composite nanofibers is mainly controlled by Fickian diffusion. Cell culture experiment verified that the composite nanofibers have higher cytotoxic effects and kill more tumor cells compared to PCL nanofibers. In summary, modifying the surface of HNT and incorporating it into PCL nanofibers can create a drug carrier with more sustained drug release and higher antitumor effects.

Improved biological performance of low modulus Ti–24Nb–4Zr–7.9Sn implants due to surface modification by anodic oxidation

Titanium oxide is believed as one of the key factors that influence the excellent corrosion properties as well as biocompatibility of titanium alloy. In the present research, thermal-electrochemical anodizing processes were performed in order to form thick layer of titanium oxide on titanium alloys (Ti6Al4V) surface. Oxidation temperature, blasting and anodizing voltage were selected as the evaluated parameters process at the present study. It was observed that temperature plays important role in the formation of oxide layer, where the thickness of the oxide increases significantly as temperature increases. However, for the case of oxide layer formed by thermal oxidation at temperature of 950oC, oxide layer on the non-blasted sample become easily peel off, whereas oxide layer on the blasted sample shows good adhesion properties. In addition, oxide layer on the blasted samples also have thicker layer as compared with oxide on the non-blasted sample. On the other hand, it was observed that further oxidation by anodizing at 43V and 63V create finer oxide layer by the filled up of porosity on the existing oxide layer. However decreasing of oxide layer thickness was also observed after anodizing, which is predicted due to the breaking up the outer oxide layer during anodizing process.