Nanotubes and nano pores with chitosan construct on TiZr serving as drug reservoir
Graphical abstract
Introduction
Extensive research investigations on the development, characterization and applications of valve metals used as implants such as titanium (Ti) have been performed due to their ease of fabrication, size control and capability to enhance various properties such as stability, biocompatibility, antibacterial effects and drug delivery [[1], [2], [3], [4]].
Although pure Ti has remarkable stability and biocompatibility and is highly praised in medical applications where direct contact to bone is required, alloying is usually employed for obtaining materials with better mechanical properties. Alloys containing other biocompatible elements such as zirconium (Zr) and niobium (Nb) and are already available in various compositions [[5], [6], [7]].
After surgery, bacterial infection and inflammation appear frequently and several drugs are administered as protection. Drugs are usually employed noninvasively by oral administration, but with the advent of nanotechnology, novel approaches were developed such as releasing the drugs directly from implants [8].
Among the many benefits of nanotechnology-based drug delivery systems is their ability to enhance the efficiency of the delivery of the therapeutic agents regarding both the loading and the controlled release as parts of improving their bioactive potential [9]. The antibiotic delivery system is also very useful after orthopedic surgery, because blood circulation is disrupted in the osseous tissue and an important volume of drug is needed during the medical treatment [10].
The existing biocompatible properties such as antibacterial effects of TiZr oxide nanotubes and nanopores [6] were further improved with enhanced stability and in vitro cell response by coating with biodegradable chitosan [11].
Chitosan coated on TiO2 nanotubes by dip coating proved its ability to extend the release of indometacin enhancing bone cell adhesion. The role of polymer thickness in controlling the drug release was demonstrated as well [12], suggesting that polymer-modified implants with nanotubular layers have the capacity to deliver a drug to a bone site over an extended period of time and with predictable kinetics. Furthermore, the described model is applicable to a wide range of drugs and implants currently used.
Gentamicin is a heat stable, bactericidal aminoglycoside antibiotic with hydroxy and amino functional groups commonly used as a prophylactic in orthopedic surgery or in various bone infections treatments [13]. Gentamicin has potentially nephrotoxic side effects but the functional groups linked through other bonds permit the fabrication of complex formulations [14,15] with nanoparticles which can mask the entrapped drug, reducing systemic toxicity. Gentamicin could be useful for developing a controlled-release formulation using biopolymers able to entrap the hydrophilic drug into less hydrophilic composites [16].
Different combinations of metals and drugs were tested for the application in orthopedy, employing Ti and Ti alloy nanotubes as vectors for the controlled release [[17], [18], [19]]. The strategy of using nanotubes as local delivery systems was proved to have important advantages due to their controlled dimension and uniformity compared to other delivery systems [12,20]. Controlled release and biocompatibility of chitosan/TiO2 nanotube array system on Ti implants were investigated in the case of constructs such as biodegradable poly(lactic-co-glycolic acid) (PLGA) [20]. Recently, new studies on the filling mechanisms and drug release were performed on drug carrier systems based on halloysite nanotubes [[21], [22], [23]].
Taking into account that TiZr is promoted as an alternative for Ti in implant research [24] and knowing [7] that TiZr alloys have a protective passive stratum of mixed oxides with the best stability and biocompatibility achieved for Ti50Zr [25], this composition was selected for the present investigation. Being effective against most species of both gram-positive and gram negative aerobic bacteria [26] through inhibition of bacteria protein synthesis, gentamicin was selected in new investigations such as therapy against gram-negative cranial bone infections [27] or in controlled release from mesoporous ZnO structures [28]. The fabrication of the nanotubes and nanopores complex construct with chitosan and gentamicin on Ti50Zr alloy has novelty and importance in establishing longer term release as an expression of better targeted treatment of bone and osteomyelitis.
The the present study is focused on the nanomaterials potential applications, investigating gentamicin loading and release as a function of dimensions and hydrophilic/hydrophobic balance of bioactive components.
Section snippets
Sample preparation
Two types of samples were prepared and investigated: nanotubular and nanoporous TiZr alloys. The TiZr samples have 50% Zr and 50% Ti and were obtained from ATI Wah Chang Co. The TiZr samples (20 × 20 x 2 mm) were first mechanically polished with a Buehler Beta equipment using SiC paper of increasing grits from P800 to P2400. Then the samples were cleaned in acetone in an ultrasonic bath for 10 min each, successively rinsed in ethanol and deionized water and dried in atmosphere. All reagents
Surface morphology
Untreated TiZr samples (Fig. 1A) exhibited a smooth surface at the nanoscale, the only marks due to the mechanical polishing being observed at a microlevel. A reproducible 3-dimensional sponge-like porosity characterized by nanosized pores (about 70 nm in diameter and 100 nm in depth) uniformly distributed across the surface was observed on samples treated with H2SO4 (Fig. 1B). Fig. 1C shows the nanotubes formed during the anodizing process. The nanotubes were fairy uniform with internal
Conclusions
The SEM investigations of complex nanotubular and nanoporous structures fabricated on Ti50Zr loaded with gentamicin and covered with chitosan revealed the expected morphological differences between the two types of surfaces in both diameter and length of the structures. Due to the differences in shapes and dimensions of the nanostructures, on the nanoporous surface, a mixed layer of GS + Chi was eventually obtained whereas on the nanotublular surface, the drug was adsorbed deeper within the
Author contributions
Conceptualization, Ioana Demetrescu and Daniela Ionita; Funding acquisition, Ioana Demetrescu; Investigation, Andrei Bogdan Stoian; Methodology, Ioana Demetrescu and Daniela Ionita; Project administration, Ioana Demetrescu; Supervision, Ioana Demetrescu; Writing – original draft, Andrei Bogdan Stoian, Ioana Demetrescu and Daniela Ionita; Writing – review & editing, Andrei Bogdan Stoian, Ioana Demetrescu and Daniela Ionita.
Funding
This research was funded by CNCSIS–UEFISCSU, project number PN-III-P4-ID PCE 2016-0316.
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgments
The SEM analyses on Quanta 650 FEGwere possible due to European Regional Development Fund through Competitiveness Operational Program 2014-2020, Priority axis 1, Project No. P_36_611, MySMIS code 107066, Innovative Technologies for Materials Quality Assurance in Health, Energy and Environmental - Center for Innovative Manufacturing Solutions of Smart Biomaterials and Biomedical Surfaces – INOVABIOMED.
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