Manpreet Bariana

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.

Tuning drug loading and release properties of diatom silica microparticles by surface modifications

Diatomaceous earth (DE), or diatomite silica microparticles originated from fossilized diatoms are a potential substitute for its silica-based synthetic counterparts to address limitations in conventional drug delivery. This study presents the impact of engineered surface chemistry of DE microparticles on their drug loading and release properties. Surface modifications with four silanes, including 3-aminopropyltriethoxy silane (APTES), methoxy-poly-(ethylene-glycol)-silane (mPEG-silane), 7-octadecyltrichlorosilane (OTS), 3-(glycidyloxypropyl)trimethoxysilane (GPTMS) and two phosphonic acids, namely 2-carboxyethyl-phosphonic acid (2 CEPA) and 16-phosphono-hexadecanoic acid (16 PHA) were explored in order to tune drug loading and release characteristics of water insoluble (indomethacin) and water soluble drugs (gentamicin). Successful grafting of these functional groups with different interfacial properties was confirmed using X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). Thermogravimetric analysis (TGA) was applied to determine the amount of loaded drugs and UV-spectrophotometry to analyse in vitro drug release from modified DE microparticles. Differences in drug release time (13-26 days) and loading capacity (14-24%) were observed depending on functional groups on the surface of DE microparticles. It was found that hydrophilic surfaces, due to the presence of polar carboxyl, amine or hydrolyzed epoxy group, favor extended release of indomethacin, while the hydrophobic DE surface modified by organic hydrocarbons gives a better sustained release profile for gentamicin. This work demonstrates that by changing surface functionalities on DE microparticles, it is possible to tune their drug loading and release characteristics for both hydrophobic and hydrophilic drugs and therefore achieve optimal drug delivery performance.

Drug-releasing implants: current progress, challenges and perspectives

The need for more efficient drug delivery strategies to treat resilient diseases and the rise of micro and nanotechnology have led to the development of more sophisticated drug-releasing implants with improved capabilities and performances for localised and controlled therapies. In recent years, implantable drug-releasing systems have emerged as an outstanding alternative to conventional clinical therapies. This new breed of implants has shown promising capabilities to overcome the inherent problems of conventional implants and therapies, making clinical treatments more efficient with minimal side effects. Recent clinical trials have demonstrated that this technology can improve the life of patients and increase their life expectancy. Within this context, this review is aimed at highlighting the different types and concepts of drug-releasing implants incorporating new nanomaterials and nanotechnology-based devices. Furthermore, the principles on which these drug-releasing implants are based as well as their advantages and limitations are discussed in detail. Finally, we provide a future perspective in the development of implantable clinical drug-delivery systems based on micro and nanotechnology.

Surface-functionalized diatom microcapsules for drug delivery of water-insoluble drugs

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.

Radiofrequency-triggered release for on-demand delivery of therapeutics from titania nanotube drug-eluting implants

AIM This study aimed to demonstrate radiofrequency (RF)-triggered release of drugs and drug carriers from drug-eluting implants using gold nanoparticles as energy transducers. MATERIALS & METHODS Titanium wire with a titania nanotube layer was used as an implant loaded with indomethacin and micelles (tocopheryl PEG succinate) as a drug and drug carrier model. RF signals were generated from a customized RF generator to trigger in vitro release. RESULTS & DISCUSSION Within 2.5 h, 18 mg (92%) of loaded drug and 14 mg (68%) of loaded drug carriers were released using short RF exposure (5 min), compared with 5 mg (31%) of drug and 2 mg (11%) of drug carriers without a RF trigger. Gold nanoparticles can effectively function as RF energy transducers inside titania nanotubes for rapid release of therapeutics at arbitrary times. CONCLUSION The results of this study show that RF is a promising strategy for triggered release from implantable drug delivery systems where on-demand delivery of therapeutics is required.

Biological response of human suture mesenchymal cells to Titania nanotube-based implants for advanced craniosynostosis therapy

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.

Glypican-based drug releasing titania implants to regulate BMP2 bioactivity as a potential approach for craniosynostosis therapy

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 15days by the glypicans released from polymer-coated TNT/Ti implants, indicating their potential application in adjunctive craniosynostosis treatment.

Nanoporous Anodic Alumina for Drug Delivery and Biomedical Applications

Nanoporous anodic alumina (NAA) engineered by simple and scalable electrochemical anodization process has been extensively explored for drug delivery (DD) and biomedical applications. This review highlights the concepts of drug-releasing implants based on NAA, with a focus on recent progress in their development and future perspectives towards advanced medical therapies, including orthopaedic and dental implants, heart/coronary/vasculature stents, immunoisolation, skin healing, tissue engineering and cell culture. The specific topics discuss the advantages of NAA carrier for drug loading and release performances, due to its unique porous structure, loading capacity, chemical inertness and biocompatibility. Finally, a conclusive overview and future perspectives are provided with suggestions about future studies that are required to have this unique biomaterial and device approved for real-life biomedical applications.