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

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 system's 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

Consume or conserve: micro-roughness of titanium implants towards fabrication of dual micro-nanotopography

Combining micro-roughness of the current titanium implants for initial stability/inter-locking with nano-topography for enhanced bioactivity/drug-release may be an ideal solution to address therapeutic challenges inside the bone micro-environment. We hereby present a single-step electrochemical anodization using conditioned electrolyte to enable fabrication of aligned titania nanopores with preserved micro-scale features of the underlying titanium implant. Applicability towards the fabrication of mechanically robust and clinically translatable next-generation of orthopaedic/dental implants with dual-topography including 'gold-standard' micro-roughness and superimposed 'bioactive' nanotopography

Predictive maintenance of bearing machinery using simulation- a bibliometric study

Modelling is a way of constructing a virtual representation of software and hardware that involves a real-world device. We will discover the behaviour of the system if the software elements of this model are guided by mathematical relationships. For testing conditions that may be difficult to replicate with hardware prototypes alone, modelling and simulation are particularly useful, especially in the early phase of the design process when hardware might not be available. Model-based approach in MATLAB-Simulink can be useful for predictive maintenance of machines as it can reduce unplanned downtimes and maintenance costs when industrial equipment breaks. Through this bibliometric paper, we carefully investigated the previously done research with the help of a number of papers from the Scopus Database. An overall analysis of the papers has been carried out to identify the extent of research done in this domain and understand the nature of the research work carried out considering the evolution of various predictive maintenance strategies being developed in recent years

Bridging the gap: optimized fabrication of robust titania nanostructures on complex implant geometries towards clinical translation

Electrochemically anodized titanium surfaces with titania nanostructures (TNS; nanopores, nanotubes, etc.) have been widely applied as therapeutic bone/dental implant modifications. Despite the numerous advancements in the field of electrochemical anodization (EA), in terms of translation into the current implant market, research gaps in this domain include the lack of fabrication optimization, performed on a substrate of conventional implant surface/geometry, and inadequate mechanical stability. In the current study, we investigate the role of substrate pre-treatment on achieving desired nanotopographies for the purpose of reproducing optimized nanostructures on the complex geometry of commercial implant surfaces, as well as in-depth mechanical stability testing of these nano-engineered coatings. The results confirmed that: (a) substrate polishing/smoothening may be insignificant with respect to fabrication of well-ordered and high quality TNS on micro-rough implants with preserved underlying micro roughness; (b) optimized outcomes can be successfully translated onto complex geometries characteristic of the current implant market, including dental implant abutments and screws (also applicable to a wider implant market including orthopaedics); (c) mechanical stability testing revealed improved modulus and hardness values as compared to conventional nanotubes/pores. We believe that such optimization advances the existing knowledge of titanium anodization and anodized implants towards integration into the current implant market and successful clinical translation. (C) 2018 Elsevier Inc. All rights reserved

Understanding and augmenting the stability of therapeutic nanotubes on anodized titanium implants

Titanium is an ideal material choice for orthopaedic and dental implants, and hence a significant amount of research has been focused towards augmenting the therapeutic efficacy of titanium surfaces. More recently the focus has shifted to nano-engineered implants fabricated via anodization to generate self-ordered nanotubular structures composed of titania (TiO2). These structures (titania nanotubes/TNTs) enable local drug delivery and tailorable cellular modulation towards achieving desirable effects like enhanced osseointegration and antibacterial action. However, the mechanical stability of such modifications is often ignored and remains under explored, and any delamination or breakage in the TNTs modification can initiate toxicity and lead to severe immuno-inflammatory reactions. This review details and critically evaluates the progress made in relation to this aspect of TNT based implants, with a focus on understanding the interface between TNTs and the implant surface, treatments aimed at augmenting mechanical stability and strategies for advanced mechanical testing within the bone micro-environment ex vivo and in vivo. This review article extends the existing knowledge in this domain of TNTs implant technology and will enable improved understanding of the underlying parameters that contribute towards mechanically robust nano-engineered implants that can withstand the forces associated with implant surgical placement and the load bearing experienced at the bone/implant interface

Estimation of anisotropic permeability in trabecular bone based on microCT imaging and pore-scale fluid dynamics simulations

Highlights - A representative volume element (RVE) size of 2 ×2 × 2 mm3 is sufficient to represent bovine trabecular bone microstructure and corresponding fluid flow properties. - Using periodic boundary conditions, with a mesh size >125,000 elements, provides the most accurate values for respective bone permeability data. - Comparison of bone specimens with respect to porosity does not provide accurate information about permeability. - For similarity between specimens based on mechanical properties, both magnitude of principal permeability and anisotropic ratio, need to be similar. - Comparison of permeabilities of our bovine sternum bone specimens with other bone samples from the literature, showed excellent agreement. Abstract In this paper, a comprehensive framework is proposed to estimate the anisotropic permeability matrix in trabecular bone specimens based on micro-computed tomography (microCT) imaging combined with pore-scale fluid dynamics simulations. Two essential steps in the proposed methodology are the selection of (i) a representative volume element (RVE) for calculation of trabecular bone permeability and (ii) a converged mesh for accurate calculation of pore fluid flow properties. Accurate estimates of trabecular bone porosities are obtained using a microCT image resolution of approximately 10 μm. We show that a trabecular bone RVE in the order of 2 × 2 × 2 mm3 is most suitable. Mesh convergence studies show that accurate fluid flow properties are obtained for a mesh size above 125,000 elements. Volume averaging of the pore-scale fluid flow properties allows calculation of the apparent permeability matrix of trabecular bone specimens. For the four specimens chosen, our numerical results show that the so obtained permeability coefficients are in excellent agreement with previously reported experimental data for both human and bovine trabecular bone samples. We also identified that bone samples taken from long bones generally exhibit a larger permeability in the longitudinal direction. The fact that all coefficients of the permeability matrix were different from zero indicates that bone samples are generally not harvested in the principal flow directions. The full permeability matrix was diagonalized by calculating the eigenvalues, while the eigenvectors showed how strongly the bone sample's orientations deviated from the principal flow directions. Porosity values of the four bone specimens range from 0.83 to 0.86, with a low standard deviation of ± 0.016, principal permeability values range from 0.22 to 1.45 ⋅ 10 −8 m2, with a high standard deviation of ± 0.33. Also, the anisotropic ratio ranged from 0.27 to 0.83, with high standard deviation. These results indicate that while the four specimens are quite similar in terms of average porosity, large variability exists with respect to permeability and specimen anisotropy. The utilized computational approach compares well with semi-analytical models based on homogenization theory. This methodology can be applied in bone tissue engineering applications for generating accurate pore morphologies of bone replacement materials and to consistently select similar bone specimens in bone bioreactor studies

Computational and experimental model of nanoengineered drug delivery system for trabecular bone

This paper describes fully coupled advective-diffusive transport of a drug through a trabecular bone sample in a perfused bioreactor. We used the analogy between heat transfer and mass transfer in order to derive the effective transport properties of the porous material such as effective diffusion coefficient and permeability. This allowed employing the heat transfer equations in Abaqus and they were solved using the finite element (FE) method. The average velocity was calculated using the Darcy-Brinkman-Forchheimer equation. Simulation results suggest that effective diffusivity plays a major role in the spatio-temporal distribution of the drug in the bone sample. Bone permeability was found less effective on manipulating the spatial distribution of drug. The bioreactor perfusion rate played a major role in the distribution of the drug throughout the bone sample. Increased perfusion rate leads to clearance of the drug towards the outlet of the bioreactor. It was found that even for moderate bioreactor perfusion rates the drug was concentrated towards the outlet, while zero concentration of drug was observed around the inlet. The numerical simulations showed that the essential effects of local drug release in bone can be captured using fluid flow through porous media theory. Our simulation results revealed that drug delivery is a multi-factorial phenomenon. Therefore, a mathematical model can enhance our understanding of this complicated problem that is difficult to characterize using experimental techniques alone

Nano-engineered titanium implants for complex bone therapies

A number of bone pathologies, such as fracture, infection or cancer, require drug therapy. However, conventional systemic drug administration is inefficient, wasteful, may not reach the target bone tissue in effective concentrations, and may cause unwanted side effects in other tissues. Ideally, drug should be delivered locally at the specific site, and in an optimal therapeutic concentration. Surface modification of the titanium implants can meet these challenges effectively by enabling effective delivery of therapeutics directly at the bone site for an extended period. Among the various suggested implant modifications, titania (TiO₂) nanotubes (TNTs), which can easily be fabricated on Ti surfaces via cost-effective electrochemical anodization, is emerging as a possible strategy for local drug delivery. This thesis describes advances in TNT/Ti implant technology towards achieving effective therapeutic and cellular modulating action from the surface of Ti wire implants, which have been nano-engineered to fabricate TNTs. The concept was to design and optimize novel therapeutic features of TNTs, using simple and scalable technologies that can ensure easy integration into implants currently on the market. Specifically, in order to address complex bone conditions such as infection, inflammation, and cancers of bone, TNTs were fabricated on Ti wires that could be inserted into bone for 3D in-bone therapeutic release. The main points of the thesis can be summarized as: 1. Structural engineering of TNTs: Periodic tailoring of the TNT structures using a modulated electrochemical anodization process in an attempt to enhance drug loading and releasing abilities of the TNTs. 2. Fabrication optimization of TNTs on curved surfaces: Optimization of anodization conditions was undertaken, with a special focus on defining the role of electrolyte ageing, in order to fabricate a mechanically robust anodic layer (TNTs) on complex curved surfaces such as Ti wires. The purpose of this was to enable easy integration of TNT technology into the current implant market, which includes widely varied geometries (pins, screws, plates, meshes, etc.). 3. Therapies for complex bone conditions: Demonstration of TNTs/Ti wire abilities to meet a range of therapeutic needs was modelled, by determining the effect of local release of osteoporotic drugs from TNTs, when inserted into collagen gels containing human osteoblasts. This was followed by analysis of the therapeutic effect on cells, and cell spread/migration morphology on the TNT surfaces. 4. Formation of chitosan-microtubes on TNTs in-situ: Investigation of the fate of chitosanmodified TNT/Ti implants in phosphate buffer (isotonic to human blood). Chitosan degradation into micro-tubes on the surface of TNTs was investigated to elucidate the mechanism underlying the in-situ formation of these novel structures. 5. Titanium (Ti) nanotubes vs titania (TiO₂) nanotubes: Conventional titania (TiO₂) nanotubes were chemically reduced into titanium while preserving the nano-topography. The converted conducting titanium nanotube implants were proposed for electrical stimulation therapy and local drug delivery. 6. TNTs on 3D printed Ti alloys: Fabrication optimization of TNTs on a unique micro-rough 3D printed Ti alloy, to enable varied surface features, including irregular micro-roughness combined with nano-topography of TNTs. Comparison was then made of cell adhesion, attachment and modulation of osteoblast function by TNTs/Ti 3D implants with conventional smooth, micro-rough and TNTs/Ti flat foil surfaces. The investigations presented in the thesis are expected to open doors towards the development of advanced in-bone therapeutic implants, in the form of easy-to-tailor nano-engineered Ti wires, with superior 3D drug releasing abilities and enhanced bone healing functionalities. The emphasis has been on designing the simplest and most cost-effective methodologies to permit easy integration into the current implant market. Applications for these implants could be in the treatment of fractures, bone infections/cancers and ‘local’ osteoporosis in bones.Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, School of Chemical Engineering, 2015