Advancing of 3D-Printed Titanium Implants with Combined Antibacterial Protection Using Ultrasharp Nanostructured Surface and Gallium-Releasing Agents.

This paper presents the development of advanced Ti implants with enhanced antibacterial activity. The implants were engineered using additive manufacturing three-dimensional (3D) printing technology followed by surface modification with electrochemical anodization and hydrothermal etching, to create unique hierarchical micro/nanosurface topographies of microspheres covered with sharp nanopillars that can mechanically kill bacteria in contact with the surface. To achieve enhanced antibacterial performance, fabricated Ti implant models were loaded with gallium nitrate as an antibacterial agent. The antibacterial efficacy of the fabricated substrates with the combined action of sharp nanopillars and locally releasing gallium ions (Ga3+) was evaluated toward Staphylococcus aureus and Pseudomonas aeruginosa. Results confirm the significant antibacterial performance of Ga3+-loaded substrates with a 100% eradication of bacteria. The nanopillars significantly reduced bacterial attachment and prevented biofilm formation while also killing any bacteria remaining on the surface. Furthermore, 3D-printed surfaces with microspheres of diameter 5-30 µm and interspaces of 12-35 µm favored the attachment of osteoblast-like MG-63 cells, as confirmed via the assessment of their attachment, proliferation, and viability. This study provides important progress toward engineering of next-generation 3D-printed implants, that combine surface chemistry and structure to achieve a highly efficacious antibacterial surface with dual cytocompatibility to overcome the limitations of conventional Ti implants.

Tailoring Additively Manufactured Titanium Implants for Short-Time Pediatric Implantations with Enhanced Bactericidal Activity.

Paediatric titanium (Ti) implants are used for the short-term fixation of fractures, after which they are removed. However, bone overgrowth on the implant surface can complicate their removal. The current Ti implants research focuses on improving their osseointegration and antibacterial properties for long-term use while overlooking the requirements of temporary implants. This paper presents the engineering of additively manufactured Ti implants with antibacterial properties and prevention of bone cell overgrowth. 3D-printed implants were fabricated followed by electrochemical anodization to generate vertically aligned titania nanotubes (TNTs) on the surface with specific diameters (∼100 nm) to reduce cell attachment and proliferation. To achieve enhanced antibacterial performance, TNTs were coated with gallium nitrate as antibacterial agent. The physicochemical characteristics of these implants assessed by the attachment, growth and viability of osteoblastic MG-63 cells showed significantly reduced cell attachment and proliferation, confirming the ability of TNTs surface to avoid cell overgrowth. Gallium coated TNTs showed strong antibacterial activity against S. aureus and P. aeruginosa with reduced bacterial attachment and high rates of bacterial death. Thus a new approach for the engineering of temporary Ti implants with enhanced bactericidal properties with reduced bone cell attachment is demonstrated as a new strategy toward a new generation of short-term implants in paediatrics.

Advancing of Additive-Manufactured Titanium Implants with Bioinspired Micro- to Nanotopographies.

There is an increasing demand for low-cost and more efficient titanium (Ti) medical implants that will provide improved osseointegration and at the same time reduce the likelihood of infection. In the past decade, additive manufacturing (AM) using metal selective laser melting (SLM) or three-dimensional (3D) printing techniques has emerged to enable novel implant geometries or properties to overcome such potential challenges. This study presents a new surface engineering approach to create bioinspired multistructured surfaces on SLM-printed Ti alloy (Ti6Al4V) implants by combining SLM technology, electrochemical anodization, and hydrothermal (HT) processes. The resulting implants display unique surfaces with a distinctive dual micro- to nano-topography composed of micron-sized spherical features, fabricated by SLM and vertically aligned nanoscale pillar structures as a result of combining anodization and HT treatment. The fabricated implants enhanced hydroxyapatite-like mineral deposition from simulated body fluid (SBF) compared to control. In addition, normal human osteoblast-like cells (NHBCs) showed strong adhesion to the nano-/microstructures and displayed greater propensity to mineralize compared to control surfaces. This engineering approach and the resulting nature-inspired multiscale-structured surface offers desired features for improving osseointegration and antibacterial performance toward the development of next-generation orthopedic and dental implants.

Engineered titanium implants for localized drug delivery: recent advances and perspectives of Titania nanotubes arrays.

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.

Diatom Silica for Biomedical Applications: Recent Progress and Advances.

Diatoms are unicellular photosynthetic algae enclosed in porous 3D nanopatterned silica enclosures called "frustules." The diatom frustules are made from biosilica self-assembled into intricate porous shells that feature unique properties including high specific surface area, biocompatibility, tailorable surface chemistry, thermal stability, and high mechanical and chemical resistance. The ability to cultivate diatoms in artificial environments and their abundant availability of diatom frustules as mineable fossilized mineral deposits (diatomite or diatomaceous earth; DE) make diatom silica a promising natural alternative to synthetic porous silica for a broad range of biomedical, environmental, agricultural, and energy applications. This review article provides a comprehensive and current account of the use of natural DE silica materials in biomedical applications focused mainly on drug delivery with some highlights on biosensing, tissue engineering, and clotting agents. The article also covers some basic physical and chemical aspects of DE material such as purification, surface chemical functionalization, biocompatibility, and cellular uptake that are critical for the development of an efficient drug carrier.

Micro- and nano-structured 3D printed titanium implants with a hydroxyapatite coating for improved osseointegration.

With the increasing demand for low-cost and more efficient dental implants, there is an urgent need to develop new manufacturing approaches and implants with better osseointegration performance. 3D printing technology provides enormous opportunities for the rapid fabrication of a new generation of patient-tailored dental implants with significantly reduced costs. This study presents the demonstration of a unique model of titanium implants based on 3D printing technology with improved osseointegration properties. Titanium alloy (Ti6Al4V) implants with a micro-structured surface are fabricated using a selective laser-melting process followed by further nano-structuring with electrochemical anodization to form titania nanotubes (TNT) and subsequent bioactivation by a hydroxyapatite (HA) coating. The osseointegration properties of the fabricated implants were examined using human primary osteoblasts and cell line models. The results showed significantly increased protein adsorption, cell adhesion and cell spreading. The expression of the late osteoblast/osteocyte genes GJA1 and PHEX was also enhanced, indicating a cell maturation effect and the promotion of mineralization on the surface. These results suggest that 3D printing technology combined with electrochemical nano-structuring and HA modification is a promising approach for the fabrication of Ti implants with improved osseointegration and provides potential alternatives to conventional dental implants.

Engineering of Micro- to Nanostructured 3D-Printed Drug-Releasing Titanium Implants for Enhanced Osseointegration and Localized Delivery of Anticancer Drugs.

Primary and secondary bone cancers are major causes of pathological bone fractures which are usually treated through implant fixation and chemotherapy. However, both approaches face many limitations. On one hand, implants may suffer from poor osseointegration, and their rejection results in repeated surgery, patient's suffering, and extensive expenses. On the other hand, there are severe systemic adverse effects of toxic chemotherapeutics which are administrated systemically. In this paper, in order to address these two problems, we present a new type of localized drug-releasing titanium implants with enhanced implants' biointegration and drug release capabilities that could provide a high concentration of anticancer drugs locally to treat bone cancers. The implants are fabricated by 3D printing of Ti alloy followed by an anodization process featuring unique micro- (particles) and nanosurface (tubular arrays) topography. We successfully demonstrate their enhanced bone osseointegration and drug loading capabilities using two types of anticancer drugs, doxorubicin (DOX) and apoptosis-inducing ligand (Apo2L/TRAIL). In vitro study showed strong anticancer efficacy against cancer cells (MDA-MB-231-TXSA), confirming that these drug-releasing implants can be used for localized chemotherapy for treatment of primary and secondary bone cancers together with fracture support.

Porous silicon for drug delivery applications and theranostics: recent advances, critical review and perspectives.

INTRODUCTION: Porous silicon (pSi) engineered by electrochemical etching has been used as a drug delivery vehicle to address the intrinsic limitations of traditional therapeutics. Biodegradability, biocompatibility, and optoelectronic properties make pSi a unique candidate for developing biomaterials for theranostics and photodynamic therapies. This review presents an updated overview about the recent therapeutic systems based on pSi, with a critical analysis on the problems and opportunities that this technology faces as well as highlighting pSi's growing potential. Areas covered: Recent progress in pSi-based research includes drug delivery systems, including biocompatibility studies, drug delivery, theranostics, and clinical trials with the most relevant examples of pSi-based systems presented here. A critical analysis about the technical advantages and disadvantages of these systems is provided along with an assessment on the challenges that this technology faces, including clinical trials and investors' support. Expert opinion: pSi is an outstanding material that could improve existing drug delivery and photodynamic therapies in different areas, paving the way for developing advanced theranostic nanomedicines and incorporating payloads of therapeutics with imaging capabilities. However, more extensive in-vivo studies are needed to assess the feasibility and reliability of this technology for clinical practice. The technical and commercial challenges that this technology face are still uncertain.

Multifunctional microspherical magnetic and pH responsive carriers for combination anticancer therapy engineered by droplet-based microfluidics.

pH stimuli responsive drug delivery platforms that can target specific locations along the gastrointestinal tract hold great promise for colorectal cancer therapy. Herein, we present a facile approach to produce microfluidic engineered pH-sensitive magnetic microspherical carriers containing multifunctional therapeutic payloads for synergistic treatment of colorectal cancer. Chemotherapeutics, 5 fluorouracil (5FU) and curcumin (CUR), were chosen due to their synergistic effect for colorectal cancer treatment and prevention. Drugs were loaded onto naturally derived porous silicon nanoparticles (SiNPs) and magnetic bacterial iron oxide nanowires (BacNWs), which acted as drug nanocontainers and magnetic elements, respectively. Drug loaded SiNPs and BacNWs were then encapsulated into polymeric microspheres using droplet-based microfluidics. To ensure controlled drug delivery into the desired site of action (colon and rectum), the microspheres were fabricated using hypromellose acetate succinate polymers, which are insoluble in the acidic medium of the stomach (i.e. pH 1.2) but soluble at basic pH (colon and rectum). Our results confirmed that the microspheres exhibit a narrow size distribution (CV > 5%) with precise size control. Moreover, in vitro dissolution and drug release data confirmed their pH-responsive properties. Motivated by these results, we explored the biocompatibility of microspheres using human RAW 264.7 macrophages. The results revealed the safety of drug free microspheres up to 1000 µg mL-1. Finally, the synergistic action of 5FU and CUR loaded microspheres was investigated on SW480 colon adenocarcinoma cells.

From The Mine to Cancer Therapy: Natural and Biodegradable Theranostic Silicon Nanocarriers from Diatoms for Sustained Delivery of Chemotherapeutics.

Drug delivery using synthetic nanoparticles including porous silicon has been extensively used to overcome the limitations of chemotherapy. However, their synthesis has many challenges such as lack of scalability, high cost, and the use of toxic materials with concerning environmental impact. Nanoscale materials obtained from natural resources are an attractive option to address some of these disadvantages. In this paper, a new mesoporous biodegradable silicon nanoparticle (SiNP) drug carrier obtained from natural diatom silica mineral available from the mining industry is presented. Diatom silica structures are mechanically fragmented and converted into SiNPs by simple and scalable magnesiothermic reduction process. Results show that SiNPs have many desirable properties including high surface area, high drug loading capacity, strong luminescence, biodegradability, and no cytotoxicity. The in-vitro release results from SiNPs loaded with anticancer drugs (doxorubicin) demonstrate a pH-dependent and sustained drug release with enhanced cytotoxicity against cancer cells. The cells study using doxorubicin loaded SiNPs shows a significantly enhanced cytotoxicity against cancer cells compared with free drug, suggesting their considerable potential as theranostic nanocarriers for chemotherapy. Their low-cost manufacturing using abundant natural materials and outstanding chemotherapeutic performance has made them as a promising alternative to synthetic nanoparticles for drug delivery applications.

Naturally Derived Iron Oxide Nanowires from Bacteria for Magnetically Triggered Drug Release and Cancer Hyperthermia in 2D and 3D Culture Environments: Bacteria Biofilm to Potent Cancer Therapeutic.

Iron oxide nanowires produced by bacteria (Mariprofundus ferrooxydans) are demonstrated as new multifunctional drug carriers for triggered therapeutics release and cancer hyperthmia applications. Iron oxide nanowires are obtained from biofilm waste in the bore system used to pump saline groundwater into the River Murray, South Australia (Australia) and processed into individual nanowires with extensive magnetic properties. The drug carrier capabilities of these iron oxide nanowires (Bac-FeOxNWs) are assessed by loading anticancer drug (doxorubicin, Dox) followed by measuring its elution under sustained and triggered release conditions using alternating magnetic field (AMF). The cytotoxicity of Bac-FeOxNWs assessed in 2D (96 well plate) and 3D (Matrigel) cell cultures using MDA-MB231-TXSA human breast cancer cells and mouse RAW 264.7 macrophage cells shows that these Bac-FeOxNWs are biocompatible even at concentrations as high as 250 µg/mL after 24 h of incubation. Finally, we demonstrate the capabilities of Bac-FeOxNWs as potential hyperthermia agent in 3D culture setup. Application of AMF increased the local temperature by 14 °C resulting in approximately 34% decrease in cell viability. Our results demonstrate that these naturally produced nanowires in the form of biofilm can efficiently act as drug carriers with triggered payload release and magnetothermal heating features for potential anticancer therapeutics 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.

Conversion of titania (TiO2) into conductive titanium (Ti) nanotube arrays for combined drug-delivery and electrical stimulation therapy.

The conversion of titania (TiO2) nanotubes into titanium (Ti), while preserving their nanotubular structures, is demonstrated. Their application as bone implants and electrodes for combined local drug delivery and electrical stimulation therapy is proposed.