Karan Gulati

Biocompatible polymer coating of titania nanotube arrays for improved drug elution and osteoblast adhesion.

Bacterial infection, extensive inflammation and poor osseointegration have been identified as the major reasons for [early] orthopaedic implant failures based on titanium. Creating implants with drug-eluting properties to locally deliver drugs is an appealing way to address some of these problems. To improve properties of titanium for orthopaedic applications, this study explored the modification of titanium surfaces with titaniananotube (TNT) arrays, and approach that combines drug delivery into bone and potentially improved bone integration. A titania layer with an array of nanotube structures (∼120 nm in diameter and 50 μm in length) was synthesized on titanium surfaces by electrochemical anodization and loaded with the water-insoluble anti-inflammatory drug indomethacin. A simple dip-coating process of polymer modification formed thin biocompatible polymer films over the drug-loaded TNTs to create TNTs with predictable drug release characteristics. Two biodegradable and antibacterial polymers, chitosan and poly(lactic-co-glycolic acid), were tested for their ability to extend the drug release time of TNTs and produce favourable bone cell adhesion properties. Dependent on polymer thickness, a significant improvement in the drug release characteristics was demonstrated, with reduced burst release (from 77% to >20%) and extended overall release from 4 days to more than 30 days. Excellent osteoblast adhesion and cell proliferation on polymer-coated TNTs compared with uncoated TNTs were also observed. These results suggest that polymer-modified implants with a TNT layer are capable of delivering a drug to a bone site over an extended period and with predictable kinetics. In addition, favourable bone cell adhesion suggests that such an implant would have good biocompatibility. The described approach is broadly applicable to a wide range of drugs and implants currently used in orthopaedic practice.

Titania nanotube arrays for local drug delivery: recent advances and perspectives

Introduction: Titania nanotube (TNTs) arrays engineered by simple and scalable electrochemical anodization process have been extensively explored as a new nanoengineering approach to address the limitations of systemic drug administration. Due to their outstanding properties and excellent biocompatibility, TNTs arrays have been used to develop new drug-releasing implants (DRI) for emerging therapies based on localized drug delivery (DD). This review highlights the concepts of DRI based on TNTs with a focus on recent progress in their development and future perspectives towards advanced medical therapies. Areas covered: Recent progress in new strategies for controlling drug release from TNTs arrays aimed at designing TNTs-based DRI with optimized performances, including extended drug release and zero-order release kinetics and remotely activated release are described. Furthermore, significant progress in biocompatibility studies on TNTs and their outstanding properties to promote hydroxyapatite and bone cells growths and to differentiate stem cells are highlighted. Examples of ex vivo and in vivo studies of drug-loaded TNTs are shown to confirm the practical and potential applicability of TNTs-based DRI for clinical studies. Finally, selected examples of preliminary clinical applications of TNTs for bone therapy and orthopedic implants, cardiovascular stents, dentistry and cancer therapy are presented. Expert opinion: As current studies have demonstrated, TNTs are a remarkable material that could potentially revolutionize localized DD therapies, especially in areas of orthopedics and localized chemotherapy. However, more extensive ex vivo and in vivo studies should be carried out before TNTs-based DRI could become a feasible technology for real-life clinical applications. This will imply the implementation of different approaches to overcome some technical and commercial challenges.

Drug-eluting Ti wires with titania nanotube arrays for bone fixation and reduced bone infection

Current bone fixation technology which uses stainless steel wires known as Kirschner wires for fracture fixing often causes infection and reduced skeletal load resulting in implant failure. Creating new wires with drug-eluting properties to locally deliver drugs is an appealing approach to address some of these problems. This study presents the use of titanium [Ti] wires with titania nanotube [TNT] arrays formed with a drug delivery capability to design alternative bone fixation tools for orthopaedic applications. A titania layer with an array of nanotube structures was synthesised on the surface of a Ti wire by electrochemical anodisation and loaded with antibiotic (gentamicin) used as a model of bone anti-bacterial drug. Successful fabrication of TNT structures with pore diameters of approximately 170 nm and length of 70 μm is demonstrated for the first time in the form of wires. The drug release characteristics of TNT-Ti wires were evaluated, showing a two-phase release, with a burst release (37%) and a slow release with zero-order kinetics over 11 days. These results confirmed our systems ability to be applied as a drug-eluting tool for orthopaedic applications. The established biocompatibility of TNT structures, closer modulus of elasticity to natural bones and possible inclusion of desired drugs, proteins or growth factors make this system a promising alternative to replace conventional bone implants to prevent bone infection and to be used for targeted treatment of bone cancer, osteomyelitis and other orthopaedic diseases.

Advanced biopolymer-coated drug-releasing titania nanotubes (TNTs) implants with simultaneously enhanced osteoblast adhesion and antibacterial properties.

Here, we report on the development of advanced biopolymer-coated drug-releasing implants based on titanium (Ti) featuring titania nanotubes (TNTs) on its surface. These TNT arrays were fabricated on the Ti surface by electrochemical anodization, followed by the loading and release of a model antibiotic drug, gentamicin. The osteoblastic adhesion and antibacterial properties of these TNT-Ti samples are significantly improved by loading antibacterial payloads inside the nanotubes and modifying their surface with two biopolymer coatings (PLGA and chitosan). The improved osteoblast adhesion and antibacterial properties of these drug-releasing TNT-Ti samples are confirmed by the adhesion and proliferation studies of osteoblasts and model Gram-positive bacteria (Staphylococcus epidermidis). The adhesion of these cells on TNT-Ti samples is monitored by fluorescence and scanning electron microscopies. Results reveal the ability of these biopolymer-coated drug-releasing TNT-Ti substrates to promote osteoblast adhesion and proliferation, while effectively preventing bacterial colonization by impeding their proliferation and biofilm formation. The proposed approach could overcome inherent problems associated with bacterial infections on Ti-based implants, simultaneously enabling the development of orthopedic implants with enhanced and synergistic antibacterial functionalities and bone cell promotion.

Nanoengineered drug-releasing Ti wires as an alternative for local delivery of chemotherapeutics in the brain

The blood–brain barrier (BBB) blocks the passage of active molecules from the blood which makes drug delivery to the brain a challenging problem. Oral drug delivery using chemically modified drugs to enhance their transport properties or remove the blocking of drug transport across the BBB is explored as a common approach to address these problems, but with limited success. Local delivery of drugs directly to the brain interstitium using implants such as polymeric wafers, gels, and catheters has been recognized as a promising alternative particularly for the treatment of brain cancer (glioma) and neurodegenerative disorders. The aim of this study was to introduce a new solution by engineering a drug-releasing implant for local drug delivery in the brain, based on titanium (Ti) wires with titania nanotube (TNT) arrays on their surfaces. Drug loading and drug release characteristics of this system were explored using two drugs commonly used in oral brain therapy: dopamine (DOPA), a neurotransmitter agent; and doxorubicin (DOXO), an anticancer drug. Results showed that TNT/Ti wires could provide a considerable amount of drugs (>170 μg to 1000 μg) with desirable release kinetics and controllable release time (1 to several weeks) and proved their feasibility for use as drug-releasing implants for local drug delivery in the brain. Purpose In this report, a new drug-releasing platform in the form of nanoengineered Ti wires with TNT arrays is proposed as an alternative for local delivery of chemotherapeutics in the brain to bypass the BBB. To prove this concept, drug loading and release characteristics of two drugs important for brain therapy (the neurotransmitter DOPA and the anticancer drug DOXO) were explored. Methods Titania nanotube arrays on the surface of Ti wires (TNT/Ti) were fabricated using a simple anodization process, followed by separate loading of two drugs (DOPA and DOXO) inside the nanotube structures. The loading and in vitro release characteristics of prepared TNT/Ti implants were examined using thermogravimetric analysis (TGA) UV-Vis spectroscopy. Results Scanning electron microscopy studies confirmed that well-ordered, vertically aligned, densely packed nanotube arrays with an average diameter of 170 nm and length 70 μm were formed on the surface of TNT/Ti wires. TGA results showed a total drug loading of 170 μg and 1200 μg inside the TNTs for DOPA and DOXO respectively. Two-phase drug release behavior was observed including a fast release (burst) for the first 6 hours and a prolonged slow release phase for 8 days, both with acceptable dosage and desirable release kinetics. The physical, structural, loading and release characteristics of prepared TNT/Ti implants showed several advantages in comparison with existing and clinically proved brain implants. Conclusion Our results confirmed that TNT/Ti wires can be successfully employed as a suitable platform to release neurotransmitters such as DOPA and anticancer drugs such as DOXO. Hence, they are a feasible alternative as drug-releasing implants for local drug delivery in the brain to combat neurodegenerative disorders or brain tumors.

Self-ordering Electrochemistry: A Simple Approach for Engineering Nanopore and Nanotube Arrays for Emerging Applications*

In this paper, we present recent work from our group focussed on the fabrication of nanopore and nanotube arrays using self-ordered electrochemistry, and their application in several key areas including template synthesis, molecular separation, optical sensing, and drug delivery. We have fabricated nanoporous anodic aluminium oxide (AAO) with controlled pore dimensions (20–200u2009nm) and shapes, and used them as templates for the preparation of gold nanorod/nanotube arrays and gold nanotube membranes with characteristic properties such as surface enhanced Raman scattering and selective molecular transport. The application of AAO nanopores as a sensing platform for reflective interferometric detection is demonstrated. Finally, a drug release study on fabricated titania nanotubes confirms their potential for implantable drug delivery applications.

Titania nanotubes for orchestrating osteogenesis at the bone-implant interface.

Titanium implants can fail due to inappropriate biomechanics at the bone-implant interface that leads to suboptimal osseointegration. Titania nanotubes (TNTs) fabricated on Ti implants by the electrochemical process have emerged as a promising modification strategy to facilitate osseointegration. TNTs enable augmentation of bone cell functions at the bone-implant interface and can be tailored to incorporate multiple functionalities including the loading of active biomolecules into the nanotubes to target anabolic processes in bone conditions such as osteoporotic fractures. Advanced functions can be introduced, including biopolymers, nanoparticles and electrical stimulation to release growth factors in a desired manner. This review describes the application of TNTs for enhancing osteogenesis at the bone-implant interface, as an alternative approach to systemic delivery of therapeutic agents.

Real-time and in Situ Drug Release Monitoring from Nanoporous Implants under Dynamic Flow Conditions by Reflectometric Interference Spectroscopy

Herein, we present an innovative approach to monitoring in situ drug release under dynamic flow conditions from aluminum implants featuring nanoporous anodic alumina (NAA) covers used as a model of drug-releasing implants. In this method, reflectometric interference spectroscopy (RIfS) is used to monitor in real-time the diffusion of drug from these nanoporous implants. The release process is carried out in a microfluidic device, which makes it possible to analyze drug release under dynamic flow conditions with constant refreshing of eluting medium. This setup mimics the physiological conditions of biological milieu at the implant site inside the host body. The release of a model drug, indomethacin, is established by measuring the optical thickness change with time under four different flow rates (i.e. 0, 10, 30, and 50 μL min(-1)). The obtained data are fitted by a modified Higuchi model, confirming the diffusion-controlled release mechanism. The obtained release rate constants demonstrate that the drug release depends on the flow rate and the faster the flow rate the higher the drug release from the nanoporous covers. In particular, the rate constants increase from 2.23 ± 0.02 to 12.47 ± 0.04 μg min(-1/2) when the flow rate is increased from 10 to 50 μL min(-1), respectively. Therefore, this method provides more reliable and relevant information than conventional in vitro drug release methods performed under static conditions.

Periodically tailored titania nanotubes for enhanced drug loading and releasing performances

The structural engineering of titania nanotubes (TNTs) using electrochemical anodization was performed to generate periodically modulated (p-TNTs) internal structures by applying an oscillatory voltage during the anodization process to demonstrate their improved drug-loading and drug-releasing properties. Drug loading and in vitro drug release studies compared with conventional TNTs with flat structures suggested considerable improvement with increased drug loading, reduced burst release and extended drug release for over 2 weeks. Furthermore, p-TNTs arrays were fractured by ultrasonication into liberated TNTs capsules and their potential applications as drug micro/nano-carriers for targeted and localized drug delivery is proposed. The presented electrochemical approach for structural engineering of TNTs provides new prospects in designing TNTs drug releasing implants with advanced drug-loading/release characteristics for localized drug delivery. Such implant modifications can further be tailored to cater for various implant challenges and bone therapies like: inflammation, infection and poor implant integration.

Anodized 3D-printed titanium implants with dual micro- and nano-scale topography promote interaction with human osteoblasts and osteocyte-like cells: 3D Printed Titanium Implants with Dual Micro- and Nano-Scale Topography

The success of implantation of materials into bone is governed by effective osseointegration, requiring biocompatibility of the material and the attachment and differentiation of osteoblastic cells. To enhance cellular function in response to the implant surface, micro‐ and nano‐scale topography have been suggested as essential. In this study, we present bone implants based on 3D–printed titanium alloy (Ti6Al4V), with a unique dual topography composed of micron‐sized spherical particles and vertically aligned titania nanotubes. The implants were prepared by combination of 3D–printing and anodization processes, which are scalable, simple and cost‐effective. The osseointegration properties of fabricated implants, examined using human osteoblasts, showed enhanced adhesion of osteoblasts compared with titanium materials commonly used as orthopaedic implants. Gene expression studies at early (day 7) and late (day 21) stages of culture were consistent with the Ti substrates inducing an osteoblast phenotype conducive to effective osseointegration. These implants with the unique combination of micro‐ and nano‐scale topography are proposed as the new generation of multi‐functional bone implants, suitable for addressing many orthopaedic challenges, including implant rejection, poor osseointegration, inflammation, drug delivery and bone healing. Copyright