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Background: Craniosynostosis is a developmental disorder characterized by the premature fusion of skull sutures, necessitating repetitive, high-risk neurosurgical interventions throughout infancy. This study used protein-releasing Titania nanotubular implant (TNT/Ti) loaded with glypican 3 (GPC3) in the cranial critical-sized defects (CSDs) in Crouzon murine model ( Fgfr2 c342y/+ knock-in mutation) to address a key challenge of delaying post-operative bone regeneration in craniosynostosis., Materials and Methods: A 3 mm wide circular CSD was created in two murine models of Crouzon syndrome: (i) surgical control (CSDs without TNT/Ti or any protein, n=6) and (ii) experimental groups with TNT/Ti loaded with GPC3, further subdivided into the presence or absence of chitosan coating (on nanotubes) (n=12 in each group). The bone volume percentage in CSDs was assessed 90 days post-implantation using micro-computed tomography (micro-CT) and histological analysis., Results: Nano-implants retrieved after 90 days post-operatively depicted well-adhered, hexagonally arranged, and densely packed nanotubes with average diameter of 120±10 nm. The nanotubular architecture was generally well-preserved. Compared with the control bone volume percentage data (without GPC3), GPC3-loaded TNT/Ti without chitosan coating displayed a significantly lower volume percent in cranial CSDs ( P <0.001). Histological assessment showed relatively less bone regeneration (healing) in GPC3-loaded CSDs than control CSDs., Conclusion: The finding of inhibition of cranial bone regeneration by GPC3-loaded TNT/Ti in vivo is an important advance in the novel field of minimally-invasive craniosynostosis therapy and holds the prospect of altering the whole paradigm of treatment for affected children. Future animal studies on a larger sample are indicated to refine the dosage and duration of drug delivery across different ages and both sexes with the view to undertake human clinical trials., Competing Interests: The authors declare no conflicts of interest in this work.

Introduction: Therapeutics delivery to bones to treat skeletal diseases or prevent postsurgical infections is challenging due to complex and solid bone structure that limits blood supply and diffusion of therapeutics administered by systemic routes to reach effective concentration. Titanium (Ti) and their alloys are employed as mainstream implant materials in orthopedics and dentistry; having superior mechanical/biocompatibility properties which could provide an alternative solution to address this problem., Areas Covered: This review presents an overview of recent development of Ti drug-releasing implants, with emphasis on nanoengineered Titania nanotubes (TNTs) structures, for solving key problems to improve implants osseointegration, overcome inflammation and infection together with providing localized drug delivery (LDD) for bone diseases including cancer. Critical analysis of the advantages/disadvantages of developed concepts is discussed, their drug loading/releasing performances and specific applications., Expert Opinion: LDD to bones can address many disorders and postsurgical conditions such as inflammation, implants rejection and infection. To this end, TNTs-Ti implants represent a potential promise for the development of new generation of multifunctional implants with drug release functions. Even this concept is extensively explored recently, there is a strong need for more preclinical studies using animal models to confirm the long-term safety and stability of TNTs-Ti implants for real-life medical applications.

Introduction: Drug delivery pertaining to acoustic cavitation generated from ultrasonic (US) irradiation is advantageous for devising smarter and more advanced therapeutics. The aim is to showcase microbubbles as drug carriers and robust theranostic for non-invasive therapies across diverse biomedical disciplines, highlighting recent technologies in this field for overcoming the blood-brain barrier (BBB) to treat cancers and neurological disorders., Areas Covered: This article reviews work on the optimized tuning of ultrasonic parameters, sonoporation, transdermal and responsive drug delivery, acoustic cavitation in vasculature and oncology, contrast imaging for real-time magnification of cell-microbubble dynamics and biomolecular targeting. Scholarly literature was sought through database search on key terminology, latest topics, reputable experts and established journals over the last five years., Expert Opinion: Cavitation offers immense promise in overcoming current diffusion and convection limitations for treating skull/brain/vascular/tissue injuries and ablating tumors to minimize chronic/acute effects. Since stable cavitation facilitates the restoration of US-opened BBB and the modulation of drug concentration, US equipment with programmable imaging modality and sensitivity are envisaged to create safer miniaturized devices for personalized care. Due to differing biomedical protocols with regard to specific medical conditions, quantitative and qualitative controls are mandatory before translation to real-life clinical applications can be accomplished.

Adverse complications associated with systemic administration of anti-cancer drugs are a major problem in cancer therapy in current clinical practice. To increase effectiveness and reduce side effects, localized drug delivery to tumour sites requiring therapy is essential. Direct delivery of potent anti-cancer drugs locally to the cancer site based on nanotechnology has been recognised as a promising alternative approach. Previously, we reported the design and fabrication of nano-engineered 3D titanium wire based implants with titania (TiO2) nanotube arrays (Ti-TNTs) for applications such as bone integration by using in-vitro culture systems. The aim of present study is to demonstrate the feasibility of using such Ti-TNTs loaded with anti-cancer agent for localized cancer therapy using pre-clinical cancer models and to test local drug delivery efficiency and anti-tumour efficacy within the tumour environment. TNF-related apoptosis-inducing ligand (TRAIL) which has proven anti-cancer properties was selected as the model drug for therapeutic delivery by Ti-TNTs. Our in-vitro 2D and 3D cell culture studies demonstrated a significant decrease in breast cancer cell viability upon incubation with TRAIL loaded Ti-TNT implants (TRAIL-TNTs). Subcutaneous tumour xenografts were established to test TRAIL-TNTs implant performance in the tumour environment by monitoring the changes in tumour burden over a selected time course. TRAIL-TNTs showed a significant regression in tumour burden within the first three days of implant insertion at the tumour site. Based on current experimental findings these Ti-TNTs wire implants have shown promising capacity to load and deliver anti-cancer agents maintaining their efficacy for cancer treatment., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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.

In this study, we present a nanoengineered therapeutic-releasing system based on aluminum wires featuring nanoporous anodic alumina layers and chitosan coatings. Nanoporous anodic alumina layers are produced on the surface of aluminum wires by electrochemical anodization. These nanoporous layers with precisely engineered nanopore geometry are used as nanocontainers for bovine serum albumin molecules labeled with fluorescein isothiocyanate (BSA-FITC), which is selected as a model drug. The surface of these therapeutic-releasing implants is coated with a biocompatible and biodegradable polymer, chitosan, in order to achieve a sustained release of protein over extended periods of time. The performance of this therapeutic-releasing device is systematically assessed through a series of experiments under static and dynamic flow conditions. In these experiments, the effect of such parameters as the number of layers of chitosan coating and the temperature and pH of the eluting medium is established. The obtained results reveal that the proposed therapeutic-releasing system based on nanoporous aluminum wires can be engineered with sustained release performance for up to 6.5 weeks, which is a critical factor for medical treatments using sensitive therapeutics such as proteins and genes when a localized delivery is desired.

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.

Here, we report a study on the biocompatibility, cell uptake and in vitro delivery of tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) by new nano-carriers called anodic alumina nanotubes (AANTs) for potential cancer therapy. AANTs were electrochemically engineered by a unique pulse anodization process, which enables precise control of the nanotube geometry, and used here as nano-carriers for drug delivery. In vitro cytotoxicity and cell uptake of AANTs was assessed using MDA-MB231-TXSA human breast cancer cells and mouse RAW 264.7 macrophage cells. AANTs exhibited excellent biocompatibility in both cell lines over a time course of five days even at a maximum concentration of AANTs of 100 μgmL(-1). Transmission electron microscopy and fluorescence microscopy confirmed a significant uptake of AANTs by RAW 264.7 cells and breast cancer cells. AANTs loaded with the pro-apoptotic protein Apo2L/TRAIL showed exceptional loading capacity (104 ± 14.4 μgmg(-1) of AANTs) and demonstrated significant decrease in viability of MDA-MB231-TXSA cancer cells due to apoptosis induction. These results demonstrate that AANTs are promising nano-carriers for drug delivery applications., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

The biomedical applications of graphene-based materials, including drug delivery, have grown rapidly in the past few years. Graphene and graphene oxide have been extensively explored as some of the most promising biomaterials for biomedical applications due to their unique properties: two-dimensional planar structure, large surface area, chemical and mechanical stability, superb conductivity and good biocompatibility. These properties result in promising applications for the design of advanced drug delivery systems and delivery of a broad range of therapeutics. In this review we present an overview of recent advances in this field of research. We briefly describe current methods for the surface modification of graphene-based nanocarriers, their biocompatibility and toxicity, followed by a summary of the most appealing examples demonstrated for the delivery of anti-cancer drugs and genes. Additionally, new drug delivery concepts based on controlling mechanisms, including targeting and stimulation with pH, chemical interactions, thermal, photo- and magnetic induction, are discussed. Finally the review is summarized, with a brief conclusion of future prospects and challenges in this field., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

In this review article we collect and analyse preparation, chemistry and properties of silica materials relevant for drug delivery applications. We review some of the most relevant milestones in the research of silica materials for implantable, oral, intravenous and dermal drug delivery systems. Preparation, chemistry and drug delivery characteristics of fumed silica nanoparticles (oral and dermal delivery route), silica xerogels (implant delivery), mesoporous silica materials (implant and oral delivery) and mesoporous silica spheres (intravenous delivery) with particular emphasis on their role in anticancer therapy and the design of stimuli responsive drug delivery systems are analysed. Recent progress in the research of silica materials for controlled drug delivery, namely, biocompatibility aspects, research on hybrid materials, anticancer and stimuli-responsive mesoporous silica materials are particularly emphasized.

The application of nanotechnology to medicine termed as 'nanomedicine' is recognised as an emerging field with enormous potential for developing new therapeutic concepts. A range of nanoscale materials have been explored in the last few years for drug delivery to address the problems associated with conventional drug therapies such as limited drug solubility, poor biodistribution, lack of selectivity and unfavourable pharmacokinetics. Among them, nanoporous materials with ordered and controlled pore structures, high surface area and pore volume, attracted great attention, particularly for implantable drug delivery systems. This review presents the recent progress in this field focused on electrochemically engineered nanopores/nanotube materials such as nanoporous alumina and nanotubular titania. The basic concept of fabrication of these unique materials using a self-ordering process, description of their structural properties, biocompatibility and recent applications for therapeutic implants is presented.

Abstract Advances in molecular biology and nanomedicine based therapies hold promise to obviate the need of multiple surgical interventions (associated with current management) in craniosynostosis by preventing bone re-ossification. One such adjunctive therapy involves application of glypicans 1 and 3 (GPC1 and GPC3) that are BMP inhibitors implicated in downregulating the BMP2 activity in prematurely fusing sutures. Electrochemically anodized Titania nanotube (TNT) arrays have been recognized as a promising localized, long-term drug delivery platform for bone-related therapies. This study presents the application of nanoengineered TNT/Ti implants loaded with recombinant glypicans for craniosynostosis therapy. By using Dual luciferase Reporter assay, we tested the biofunctionality of eluted glypicans from the TNT/Ti implants for BMP2 bioactivity regulation in C2C12 murine myoblast cell line. BMP2 activity was inhibited significantly for up to 15 days by the glypicans released from polymer-coated TNT/Ti implants, indicating their potential application in adjunctive craniosynostosis treatment. Graphical Abstract Titania nanotube- based protein delivery implants have been assessed in vitro to provide a sustained release of bone inhibiting glypicans (rGPC1 and rGPC3). The bioactivity of released glypicans was confirmed by downregulation of BMP2 expression in transfected C2C12 cells. Image 1 Highlights • Titania nanotubes (TNTs) implants have been engineered by electrochemical process. • TNTs glypican releasing implants have been prepared and evaluated. • BMP2 activity was inhibited significantly for up to 15 days by these implants. • The potential for craniosynostosis therapy is proposed by this approach. [ABSTRACT FROM AUTHOR]

The use of conventional therapy based on a single therapeutic agent is not optimal to treat human diseases. The concept called 'combination therapy', based on simultaneous administration of multiple therapeutics is recognized as a more efficient solution. Interestingly, this concept has been in use since ancient times in traditional herbal remedies with drug combinations, despite mechanisms of these therapeutics not fully comprehended by scientists. This idea has been recently re-enacted in modern scenarios with the introduction of polymeric micelles loaded with several drugs as multidrug nanocarriers. This Concept article presents current research and developments on the application of polymeric micelles for multidrug delivery and combination therapy. The principles of micelle formation, their structure, and the developments and concept of multidrug delivery are introduced, followed by discussion on recent advances of multidrug delivery concepts directed towards targeted drug delivery and cancer, gene, and RNA therapies. The advantages of various polymeric micelles designed for different applications, and new developments combined with diagnostics and imaging are elucidated. A compilation work from our group based on multidrug-loaded micelles as carriers in drug-releasing implants for local delivery systems based on titania nanotubes is summarized. Finally, an overview of recent developments and prospective outlook for future trends in this field is given. [ABSTRACT FROM AUTHOR]

Naturally available and biocompatible materials are potential substitutes for synthetic mesoporous materials as suitable drug carriers for the development of cost-effective drug delivery systems. This work investigates the application of a porous silica material derived from diatoms, also known as diatomaceous earth. The aim is to explore the surface functionalization of diatom microcapsules and their impact on the drug loading and release characteristics of water-insoluble drugs. Indomethacin was used as the model for poorly soluble drug. The surface modification on diatoms was performed with two organosilanes; 3-aminopropyltriethoxy silane and N-(3-(trimethoxysilyl) propyl) ethylene diamine and phosphonic acids (2-carboxyethyl-phosphonic acid and 16-phosphono-hexadecanoic acid) providing organic surface hydrophilic and hydrophobic properties. Extensive characterizations using scanning electron microscopy, X-ray photoelectron spectroscopy and differential scanning calorimetry was performed to confirm covalent grafting of monolayer aminosilane and phosphonic acid on the diatom surfaces. Differences in loading capacity of diatoms (15–24%) and release time (6–15 days) were observed which is due to the presence of different functional groups on the surface. It was found that 2-carboxyethyl-phosphonic acid, 3-aminopropyltriethoxy silane and N-(3-(trimethoxysilyl) propyl) ethylene diamine render diatom surfaces hydrophilic, due to polar carboxyl functional group (COOH) and active amine species (NH and NH2) that favor drug adsorption; better encapsulation efficiency and prolonged release of drugs, over the hydrophobic surface created by 16-phosphono-hexadecanoic acid. This work demonstrates diatom porous silica as a promising drug carrier, with possibility to further improve their performances by tailoring their surface functionalities to achieve the required drug loading and release characteristics for different therapeutic conditions. [ABSTRACT FROM AUTHOR]

Abstract: A non-invasive and external stimulus-driven local drug delivery system (DDS) based on titania nanotube (TNT) arrays loaded with drug encapsulated polymeric micelles as drug carriers and ultrasound generator is described. Ultrasound waves (USW) generated by a pulsating sonication probe (Sonotrode) in phosphate buffered saline (PBS) at pH 7.2 as the medium for transmitting pressure waves, were used to release drug-loaded nano-carriers from the TNT arrays. It was demonstrated that a very rapid release in pulsatile mode can be achieved, controlled by several parameters on the ultrasonic generator. This includes pulse length, time, amplitude and power intensity. By optimization of these parameters, an immediate drug-micelles release of 100% that spans a desirable time of 5–50min was achieved. It was shown that stimulated release can be generated and reproduced at any time throughout the TNT-Ti implant life, suggesting considerable potential of this approach as a feasible and tunable ultrasound-mediated drug delivery system in situ via drug-releasing implants. It is expected that this concept can be translated from an in vitro to in vivo regime for therapeutic applications using drug-releasing implants in orthopedic and coronary stents. [Copyright &y& Elsevier]

Diatom silica microcapsules prepared by purification of diatomaceous earth (DE) were functionalised by dopamine modified iron-oxide nanoparticles, in order to introduce diatoms with magnetic properties. The application of magnetised diatoms as magnetically guided drug delivery microcarriers has been demonstrated. [ABSTRACT FROM AUTHOR]

Highlights: [•] The use of natural porous silica from diatoms for drug delivery is described. [•] Their surface modification with silanes and phosphonic acid is demonstrated. [•] The drug loading and release of two model drugs was successfully demonstrated. [•] The chemical modification and particle size have influence on drug release. [•] Diatom silica is promising new biomaterial for pharmaceutical applications. [Copyright &y& Elsevier]

Dendrimers are nano-sized and three-dimensional macromolecules with well-defined globular architecture and are widely used in various aspects such as drug and gene delivery owing to multivalent and host-guest entrapment properties. However, dendrimers like other nanomaterials have some disadvantages for example rapid clearance by reticuloendothelial system, toxicity due to interaction of amine terminated group with cell membrane, low transfection efficiency and lack of controlled release behavior, which reduce their therapeutic efficiency. To solve these problems, surface functionalization of dendrimers can be carried out. Surface functionalization not only mitigates this obstacle but also renders excessive specificity to dendrimer to improve efficiency of cancer therapy. Specific properties in cancer cell compared to normal cells such as overexpression of various receptors and difference in biological condition like pH, temperature and redox of tumor environment can be an appropriate strategy to increase site-specific targeting efficiency. Therefore, in this article we focus on numerous functionalization strategies, which are used in the modification of dendrimers through attachment of lipid, amino acid, protein/peptide, aptamer, vitamin, antibody. Moreover, increased biocompatibility, site-specific delivery based on various ligands, enhanced transfection efficiency, sustained and controlled release behavior based on stimuli responsiveness are benefits of functionalized dendrimer which we discuss in this review. Overall, these functionalized dendrimers can open a new horizon in the field of targeted drug and gene delivery. [ABSTRACT FROM AUTHOR]

Titania nanotubes (TNTs) engineered on titanium (Ti) surfaces (i.e. TNT/Ti) and loaded with specific drugs have been recognised as a promising solution for localised therapeutic delivery to address several medical problems not feasible with conventional drug administration. We propose the use of TNT/Ti protein-releasing implants to treat paediatric craniofacial abnormality in craniosynostosis caused by premature fusion of cranial sutures. In this study, we have analysed the biological response of human suture mesenchymal cells (SMCs), extracted from two different patients undergoing craniofacial reconstruction surgery, at the TNT/Ti implant surface. The experimental groups included large-diameter TNT/Ti implants, with and without biopolymer surface coating (Chitosan and Pluronic-F127) while the controls comprised of flat Ti disc and tissue culture plastic. The non-loaded implant surfaces and the cellular interactions at the implant-cell interface were characterised using scanning electron microscopy (SEM). The SMC adhesion, viability and proliferation were determined by MTT assay and manual cell counting at day 1 and day 3 of cell incubation. SEM showed significant reduction in initial attachment and adhesion of SMCs at TNT-cell biointerface compared with the control Ti discs. Subsequent cell proliferation results also revealed a decrease in the number of viable cells on the TNT surfaces. The nanotopography and structural features along with the surface chemistry dictated the cellular response, with nanotubular surfaces (with and without polymer coating) impeding cell adhesion and proliferation. Our findings hold promise for the use of TNT-based cranial implants as a delivery system to prevent sutural bone growth for advanced craniosynostosis therapy. [ABSTRACT FROM AUTHOR]

Herein, we report on a rational electrochemical approach based on pulse anodization (PA) of aluminum for the fabrication of ultra-short anodic alumina nanotubes (AANTs) with exquisitely controlled dimensions. AANTs with average length 485 ± 180 nm and outer diameter 90 ± 10 nm were fabricated by PA with 0.3 M sulfuric acid and 10% ethanol. Our findings suggest that extensive Joule's heat generation at the nanopore's base is critical for optimized AANTs' liberation from pulse-anodized anodic aluminum oxide (AAO) nanostructure. The heat evolution results in an enhanced oxygen generation and a rapid voltage recovery during PA. While oxygen generation weakens the conjunction between cells, rapid voltage recovery generates asynchronous inner/outer wall structural modulation, which consequently facilitates structural cleavage of nanotubes along mild anodization/hard anodization (MA/HA) interfaces after acid etching. The understanding of AANTs fabrication mechanism enables us for the first time to fabricate ultra-short AANTs by reducing HA duration down to 1 second and using ethanol for enhancing heat generation. The resulting AANTs with controlled dimensions and high liberation yield offer new opportunities for advanced applications such as catalysis, template-assisted nanofabrication, optical sensing and drug delivery. [ABSTRACT FROM AUTHOR]

Review: <100 refs. [ABSTRACT FROM AUTHOR]

Abstract: The use of porous silica microshells (microparticles) generated from fossilised diatoms known as diatomite or diatomaceous earth (DE) as a natural drug carrier for drug delivery application is presented. The structure, morphology, particle size distribution, porosity, surface area and crystallinity of diatom microshells obtained from Australian mine (Mount Sylvia Diatomite Pty. Ltd.) were characterised using scanning electron microscopy, particle size measurements, BET analysis and X-ray powder diffraction analysis. To prove the drug delivery concept based on diatoms for implant and oral drug delivery, indomethacin as a model of water poorly soluble drug was investigated. Results show the effectiveness of diatom silica for drug delivery application, with about 22wt.% drug loading capacity and sustained drug release over two weeks. Two steps drug release from diatom structures were observed: the first is rapid release (over 6h) attributed to the surface deposited drug and the second is slow and sustained release over two weeks with zero order kinetics, as a result of release from diatom pores and internal hollow structure. These results confirm that natural material based on diatom silica can be successfully applied as a biocarrier for both oral and implant drug delivery applications, offering considerable potential to replace synthetic silica based materials. [Copyright &y& Elsevier]

Abstract: Nanotubular titanium oxide (TiO2) produced by self-ordering processes using electrochemical anodization have been extensively explored in recent years as a new biomaterial for implants, drug delivery systems, cell growth, biosensors, immunoisolations, bioartificial organs and tissue engineering. Chemical inertness is the main weakness of this material when placed in contact with biological systems and surface modification is a possible solution of this problem. The aim of this study is to develop a flexible and facile method for surface modification of TiO2 nanotubes to tailor new interfacial properties important in many biomedical applications. TiO2 nanotubes were prepared by electrochemical anodization of titanium foil using ethylene glycol: NH4F electrolyte (2% water and 0.3% NH4F). Plasma surface modification using allylamine (AA) as a precursor has been applied to generate a thin and chemically reactive polymer (AAPP) film rich in amine groups on top of the TiO2 nanotube surface. This initial polymer film was used for further surface functionalization by attachment of desired molecules. Two modification techniques were used to demonstrate the flexibility for building of new functionalities on titania nanotube surface: electrostatic adsorption of poly(sodium styrenesulfonate) (PSS) as an example of layer-by-layer assembly (LbL), and covalent coupling of poly(ethylene glycol) (PEG) as an example of creating a protein-resistant surface. These approaches for tailoring the surface chemistry and wettability of TiO2 nanotubes offer considerable prospects for advancing their interfacial properties to improve existing and develop new functional biomaterials for diverse biomedical applications. [Copyright &y& Elsevier]