Nano-engineered titanium implants for complex bone therapies

Abstract

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.