Load, unload and repeat: Understanding the mechanical characteristics of zirconia in dentistry.

OBJECTIVES: Zirconia-based dental restorations and implants are gaining attention due to their bioactivity, corrosion resistance and mechanical stability. Further, surface modification of zirconia implants has been performed at the macro-, micro- and nanoscale to augment bioactivity. While zirconia's physical and chemical characteristics have been documented, its relation to mechanical performance still needs to be explored. This extensive review aims to address this knowledge gap. METHODS: This review critically compares and contrasts the findings from articles published in the domain of 'mechanical stability of zirconia\ in dentistry' based on a literature survey (Web of Science, Medline/PubMed and Scopus databases) and a review of the relevant publications in international peer-reviewed journals. Reviewing the published data, the mechanical properties of zirconia, such as fracture resistance, stress/tension, flexural strength, fatigue, and wear are detailed and discussed to understand the biomechanical compatibility of zirconia with the mechanical performance of modified zirconia in dentistry also explored. RESULTS: A comprehensive insight into dental zirconia's critical fundamental mechanical characteristics and performance is presented. Further, research challenges and future directions in this domain are recommended. SIGNIFICANCE: This review extends existing knowledge of zirconia's biomechanical performance and it they can be modulated to design the next generation of zirconia dental restorations and implants to withstand long-term constant loading.

Microvesicle-eluting nano-engineered implants influence inflammatory response of keratinocytes.

Besides enhancing osseo- and soft tissue integration, modulating inflammation at the implant site is also crucial for dental implant success. Uncontrolled peri-implant inflammation can cause significant loss of surrounding tissue and implant failure. It was recently shown that microvesicles (MVs), a less-studied type of extracellular vesicles, play a crucial role in cell-to-cell communication and may modulate angiogenesis and inflammatory response. The effect of MVs on regulating inflammation at an implant site, however, remains unexplored. In the current study, MVs were isolated and characterised from human primary gingival fibroblasts (hGFs) and loaded within titania nanotubes (TNTs, fabricated via anodisation on 3D Ti wire implants) towards their local release. The modified implants were characterised using SEM and confocal imaging to confirm the loading and local release of MVs from TNTs. In vitro studies demonstrated the internalisation of hGFs-MVs by human gingival keratinocytes (OKF6/TERT2 cell line), which caused a significant reduction in the production of pro-inflammatory cytokines. The results support MVs-releasing TNTs as a promising implant surface modification strategy to reduce inflammation, paving the way for further advancements in therapeutic dental implants.

Profiling to Probing: Atomic force microscopy to characterize nano-engineered implants.

Surface modification of implants in the nanoscale or implant nano-engineering has been recognized as a strategy for augmenting implant bioactivity and achieving long-term implant success. Characterizing and optimizing implant characteristics is crucial to achieving desirable effects post-implantation. Modified implant enables tailored, guided and accelerated tissue integration; however, our understanding is limited to multicellular (bulk) interactions. Finding the nanoscale forces experienced by a single cell on nano-engineered implants will aid in predicting implants' bioactivity and engineering the next generation of bioactive implants. Atomic force microscope (AFM) is a unique tool that enables surface characterization and understanding of the interactions between implant surface and biological tissues. The characterization of surface topography using AFM to gauge nano-engineered implants' characteristics (topographical, mechanical, chemical, electrical and magnetic) and bioactivity (adhesion of cells) is presented. A special focus of the review is to discuss the use of single-cell force spectroscopy (SCFS) employing AFM to investigate the minute forces involved with the adhesion of a single cell (resident tissue cell or bacterium) to the surface of nano-engineered implants. Finally, the research gaps and future perspectives relating to AFM-characterized current and emerging nano-engineered implants are discussed towards achieving desirable bioactivity performances. This review highlights the use of advanced AFM-based characterization of nano-engineered implant surfaces via profiling (investigating implant topography) or probing (using a single cell as a probe to study precise adhesive forces with the implant surface). STATEMENT OF SIGNIFICANCE: Nano-engineering is emerging as a surface modification platform for implants to augment their bioactivity and achieve favourable treatment outcomes. In this extensive review, we closely examine the use of Atomic Force Microscopy (AFM) to characterize the properties of nano-engineered implant surfaces (topography, mechanical, chemical, electrical and magnetic). Next, we discuss Single-Cell Force Spectroscopy (SCFS) via AFM towards precise force quantification encompassing a single cell's interaction with the implant surface. This interdisciplinary review will appeal to researchers from the broader scientific community interested in implants and cell adhesion to implants and provide an improved understanding of the surface characterization of nano-engineered implants.

Fit and forget: The future of dental implant therapy via nanotechnology.

Unlike orthopedic implants, dental implants require the orchestration of both osseointegration at the bone-implant interface and soft-tissue integration at the transmucosal region in a complex oral micro-environment with ubiquitous pathogenic bacteria. This represents a very challenging environment for early acceptance and long-term survival of dental implants, especially in compromised patient conditions, including aged, smoking and diabetic patients. Enabling advanced local therapy from the surface of titanium-based dental implants via novel nano-engineering strategies is emerging. This includes anodized nano-engineered implants eluting growth factors, antibiotics, therapeutic nanoparticles and biopolymers to achieve maximum localized therapeutic action. An important criterion is balancing bioactivity enhancement and therapy (like bactericidal efficacy) without causing cytotoxicity. Critical research gaps still need to be addressed to enable the clinical translation of these therapeutic dental implants. This review informs the latest developments, challenges and future directions in this domain to enable the successful fabrication of clinically-translatable therapeutic dental implants that would allow for long-term success, even in compromised patient conditions.

Craniofacial therapy: advanced local therapies from nano-engineered titanium implants to treat craniofacial conditions.

Nano-engineering-based tissue regeneration and local therapeutic delivery strategies show significant potential to reduce the health and economic burden associated with craniofacial defects, including traumas and tumours. Critical to the success of such nano-engineered non-resorbable craniofacial implants include load-bearing functioning and survival in complex local trauma conditions. Further, race to invade between multiple cells and pathogens is an important criterion that dictates the fate of the implant. In this pioneering review, we compare the therapeutic efficacy of nano-engineered titanium-based craniofacial implants towards maximised local therapy addressing bone formation/resorption, soft-tissue integration, bacterial infection and cancers/tumours. We present the various strategies to engineer titanium-based craniofacial implants in the macro-, micro- and nano-scales, using topographical, chemical, electrochemical, biological and therapeutic modifications. A particular focus is electrochemically anodised titanium implants with controlled nanotopographies that enable tailored and enhanced bioactivity and local therapeutic release. Next, we review the clinical translation challenges associated with such implants. This review will inform the readers of the latest developments and challenges related to therapeutic nano-engineered craniofacial implants.

Enhanced Corrosion Resistance and Local Therapy from Nano-Engineered Titanium Dental Implants.

Titanium is the ideal material for fabricating dental implants with favorable biocompatibility and biomechanics. However, the chemical corrosions arising from interaction with the surrounding tissues and fluids in oral cavity can challenge the integrity of Ti implants and leach Ti ions/nanoparticles, thereby causing cytotoxicity. Various nanoscale surface modifications have been performed to augment the chemical and electrochemical stability of Ti-based dental implants, and this review discusses and details these advances. For instance, depositing nanowires/nanoparticles via alkali-heat treatment and plasma spraying results in the fabrication of a nanostructured layer to reduce chemical corrosion. Further, refining the grain size to nanoscale could enhance Ti implants' mechanical and chemical stability by alleviating the internal strain and establishing a uniform TiO2 layer. More recently, electrochemical anodization (EA) has emerged as a promising method to fabricate controlled TiO2 nanostructures on Ti dental implants. These anodized implants enhance Ti implants' corrosion resistance and bioactivity. A particular focus of this review is to highlight critical advances in anodized Ti implants with nanotubes/nanopores for local drug delivery of potent therapeutics to augment osseo- and soft-tissue integration. This review aims to improve the understanding of novel nano-engineered Ti dental implant modifications, focusing on anodized nanostructures to fabricate the next generation of therapeutic and corrosion-resistant dental implants. The review explores the latest developments, clinical translation challenges, and future directions to assist in developing the next generation of dental implants that will survive long-term in the complex corrosive oral microenvironment.

Advancing Nitinol: From heat treatment to surface functionalization for nickel-titanium (NiTi) instruments in endodontics.

Nickel-titanium (NiTi) alloy has been extensively researched in endodontics, particularly in cleaning and shaping the root canal system. Research advances have primarily focused on the design, shape, and geometry of the NiTi files as well as metallurgy and mechanical properties. So far, extensive investigations have been made surrounding surface and thermomechanical treatments, however, limited work has been done in the realm of surface functionalization to augment its performance in endodontics. This review summarizes the unique characteristics, current use, and latest developments in thermomechanically treated NiTi endodontic files. It discusses recent improvements in nano-engineering and the possibility of customizing the NiTi file surface for added functionalization. Whilst clinical translation of this technology has yet to be fully realized, future research direction will lie in the use of nanotechnology.

Influence of Clinical Decontamination Techniques on the Surface Characteristics of SLA Titanium Implant.

The study aims: 1. To perform diode laser, titanium (Ti) brush, and Ti curette treatment on sandblasted and acid-etched (SLA) Ti surfaces, with/without H2O2 and CHX, 2. To investigate the influence of decontamination techniques on implant surface topography and hydrophilicity. Diode laser, Ti brush, and Ti curette treatments were performed on the Grade 4 Ti discs, with/without treatment with 3% H2O2 solution or 0.2% CHX. Surface characteristics were investigated via SEM, optical profilometry, and water contact angle meter. SEM findings revealed flat and scratched areas when treated with Ti curette and Ti brush. For diode laser, SEM showed melting in specific areas. Ra and Rt values were lower in all test groups than in the control group (p < 0.05). The adjunctive chemical treatment showed negligible effects in SEM images and surface roughness measurements compared to laser and mechanical treatment-only groups. H2O2 treatment resulted in enhanced hydrophilicity in either treatment modalities with a significant difference compared to the negative control group (p < 0.05). In all test groups, the hydrophilicity was enhanced compared to the negative control group (p < 0.05). Diode laser treatment had the least disruptive effect on the Ti surface characteristics. The use of other mechanical methods caused significant alterations in the surface roughness.

Understanding the influence of electrolyte aging in electrochemical anodization of titanium.

Titania nanotubes or nanopores self-ordered on electrochemically anodized (EA) titanium have been widely applied towards photocatalysis, solar cells, purification and biomedical implants. As a result, significant research has been focused towards optimizing anodization to fabricate controlled, stable and reproducible nanostructures. Among these, the use of organic-based electrolyte, like ethylene glycol (with NH4F and water), to anodize Ti has been widely applied and researched. Interestingly, among the various influencing EA factors, electrolyte aging (repeated EA using non-target Ti, prior to EA of target Ti substrate) has been underexplored, with only few studies aiming to optimize electrolyte aging and its influence on the nanostructures fabricated. Moreover, many research laboratories utilize electrolyte aging in Ti anodization, but this practice is seldom reported. In this extensive and pioneering review, we discuss and detail electrolyte aging in Ti anodization to fabricate controlled nanostructures, and its influence on nanostructure characteristics including morphology, chemistry, stability and application-specific performance. This review will inform future research aimed at optimizing electrolyte aging and Ti anodization to fabricate controlled nanostructures catering to specific application needs.

Advancing dental implants: Bioactive and therapeutic modifications of zirconia.

Zirconium-based implants have gained popularity in the dental implant field owing to their corrosion resistance and biocompatibility, attributed to the formation of a native zirconia (ZrO2) film. However, enhanced bioactivity and local therapy from such implants are desirable to enable the earlier establishment and improved long-term maintenance of implant integration, especially in compromised patient conditions. As a result, surface modification of zirconium-based implants have been performed using various physical, chemical and biological techniques at the macro-, micro-, and nano-scales. In this extensive review, we discuss and detail the development of Zr implants covering the spectrum from past and present advancements to future perspectives, arriving at the next generation of highly bioactive and therapeutic nano-engineered Zr-based implants. The review provides in-depth knowledge of the bioactive/therapeutic value of surface modification of Zr implants in dental implant applications focusing on clinical translation.

Novel Nano-Engineered Biomaterials for Bone Tissue Engineering.

This Special Issue of Nanomaterials explores the recent advances relating to nano-engineered strategies for biomaterials and implants in bone tissue engineering [...].

Nano-Engineering Solutions for Dental Implant Applications.

This Special Issue of Nanomaterials explores the recent advances and trends with respect to nano-engineered strategies towards dental implant applications [...].

Research to Clinics: Clinical Translation Considerations for Anodized Nano-Engineered Titanium Implants.

Titania nanotubes (TNTs) fabricated on titanium orthopedic and dental implants have shown significant potential in "proof of concept" in vitro, ex vivo, and short-term in vivo studies. However, most studies do not focus on a clear direction for future research towards clinical translation, and there exists a knowledge gap in identifying key research challenges that must be addressed to progress to the clinical setting. This review focuses on such challenges with respect to anodized titanium implants modified with TNTs, including optimized fabrication on clinically utilized microrough surfaces, clinically relevant bioactivity assessments, and controlled/tailored local release of therapeutics. Further, long-term in vivo investigations in compromised animal models under loading conditions are needed. We also discuss and detail challenges and progress related to the mechanical stability of TNT-based implants, corrosion resistance/electrochemical stability, optimized cleaning/sterilization, packaging/aging, and nanotoxicity concerns. This extensive, clinical translation focused review of TNTs modified Ti implants aims to foster improved understanding of key research gaps and advances, informing future research in this domain.

Influence of Bioinspired Lithium-Doped Titanium Implants on Gingival Fibroblast Bioactivity and Biofilm Adhesion.

Soft tissue integration (STI) at the transmucosal level around dental implants is crucial for the long-term success of dental implants. Surface modification of titanium dental implants could be an effective way to enhance peri-implant STI. The present study aimed to investigate the effect of bioinspired lithium (Li)-doped Ti surface on the behaviour of human gingival fibroblasts (HGFs) and oral biofilm in vitro. HGFs were cultured on various Ti surfaces-Li-doped Ti (Li_Ti), NaOH_Ti and micro-rough Ti (Control_Ti)-and were evaluated for viability, adhesion, extracellular matrix protein expression and cytokine secretion. Furthermore, single species bacteria (Staphylococcus aureus) and multi-species oral biofilms from saliva were cultured on each surface and assessed for viability and metabolic activity. The results show that both Li_Ti and NaOH_Ti significantly increased the proliferation of HGFs compared to the control. Fibroblast growth factor-2 (FGF-2) mRNA levels were significantly increased on Li_Ti and NaOH_Ti at day 7. Moreover, Li_Ti upregulated COL-I and fibronectin gene expression compared to the NaOH_Ti. A significant decrease in bacterial metabolic activity was detected for both the Li_Ti and NaOH_Ti surfaces. Together, these results suggest that bioinspired Li-doped Ti promotes HGF bioactivity while suppressing bacterial adhesion and growth. This is of clinical importance regarding STI improvement during the maintenance phase of the dental implant treatment.

Dental Implant Nano-Engineering: Advances, Limitations and Future Directions.

Titanium (Ti) and its alloys offer favorable biocompatibility, mechanical properties and corrosion resistance, which makes them an ideal material choice for dental implants. However, the long-term success of Ti-based dental implants may be challenged due to implant-related infections and inadequate osseointegration. With the development of nanotechnology, nanoscale modifications and the application of nanomaterials have become key areas of focus for research on dental implants. Surface modifications and the use of various coatings, as well as the development of the controlled release of antibiotics or proteins, have improved the osseointegration and soft-tissue integration of dental implants, as well as their antibacterial and immunomodulatory functions. This review introduces recent nano-engineering technologies and materials used in topographical modifications and surface coatings of Ti-based dental implants. These advances are discussed and detailed, including an evaluation of the evidence of their biocompatibility, toxicity, antimicrobial activities and in-vivo performances. The comparison between these attempts at nano-engineering reveals that there are still research gaps that must be addressed towards their clinical translation. For instance, customized three-dimensional printing technology and stimuli-responsive, multi-functional and time-programmable implant surfaces holds great promise to advance this field. Furthermore, long-term in vivo studies under physiological conditions are required to ensure the clinical application of nanomaterial-modified dental implants.

Influence of sterilization on the performance of anodized nanoporous titanium implants.

Towards clinical translation of bioactive nano-engineered titanium implants, achieving appropriate sterilization and understanding its influence on the modified implant characteristics is essential. With limited studies exploring the influence of sterilization techniques on electrochemically anodized titanium with TiO2 nanostructures, we aimed to advance this domain by performing an in-depth evaluation of the influence of common sterilization techniques (ethanol immersion, various UV irradiation times, gamma irradiation, and dry/wet autoclaving) on TiO2 nanopores fabricated on micro-rough Ti surfaces (dual micro-nano) via single step anodization. Various sterilized surfaces were systematically compared in terms of topographical, chemical, crystalline, wettability and mechanical characteristics. Next, we investigated the protein adhesion capacity and functions of primary gingival fibroblasts (proliferation, adhesion/alignment and spreading morphology) to compare the bioactivity of the sterilized nanopores. Ethanol immersion, gamma irradiation and UV irradiation conserved the topography of the fabricated nanopores, while autoclave sterilization (both dry and wet) compromised the nanoporous structures. Various duration of UV-sterilization resulted in no significant changes in the surface topography and chemistry of the fabricated TNPs. Our findings revealed that UV irradiation is the most appropriate technique to sterilize nano-engineered titanium implants for appropriate wettability, protein adhesion capacity and enhanced metabolism and proliferation of human gingival fibroblasts (hGFs). This study systematically investigated the influence of sterilization on anodized nano-engineered titanium implants towards achieving reproducible outcomes (in terms of topography, chemistry and bioactivity), and found that UV irradiation holds great promise for application across different nano-engineered metal surfaces.

Periodontal and Dental Pulp Cell-Derived Small Extracellular Vesicles: A Review of the Current Status.

Extracellular vesicles (EVs) are membrane-bound lipid particles that are secreted by all cell types and function as cell-to-cell communicators through their cargos of protein, nucleic acid, lipids, and metabolites, which are derived from their parent cells. There is limited information on the isolation and the emerging therapeutic role of periodontal and dental pulp cell-derived small EVs (sEVs, <200 nm, or exosome). In this review, we discuss the biogenesis of three EV subtypes (sEVs, microvesicles and apoptotic bodies) and the emerging role of sEVs from periodontal ligament (stem) cells, gingival fibroblasts (or gingival mesenchymal stem cells) and dental pulp cells, and their therapeutic potential in vitro and in vivo. A review of the relevant methodology found that precipitation-based kits and ultracentrifugation are the two most common methods to isolate periodontal (dental pulp) cell sEVs. Periodontal (and pulp) cell sEVs range in size, from 40 nm to 2 µm, due to a lack of standardized isolation protocols. Nevertheless, our review found that these EVs possess anti-inflammatory, osteo/odontogenic, angiogenic and immunomodulatory functions in vitro and in vivo, via reported EV cargos of EV-miRNAs, EV-circRNAs, EV-mRNAs and EV-lncRNAs. This review highlights the considerable therapeutic potential of periodontal and dental pulp cell-derived sEVs in various regenerative applications.

Double-edged sword: Therapeutic efficacy versus toxicity evaluations of doped titanium implants.

Titanium-based orthopaedic/dental implants modified with various metal-doping strategies can enhance local therapy and bioactivity. Intentional or unintentional (because of loading and wear) release of metal ions/nanoparticles (NPs) from metal-doped implants can be therapeutic or cause adverse local tissue reactions, compromising long-term survival. Strategies to incorporate metals into implants, such as superficial or deep loading inside nano-engineered surfaces, including nanotubes, and the physiochemical characteristics of the released species significantly influence both their therapeutic and cytotoxic potential. In this review, we compare and contrast this 'double-edged sword' to arrive at an improved understanding of metal-doped implants to enable controlled therapy while minimising cytotoxicity concerns.

Micro + Nano: Conserving the Gold Standard Microroughness to Nanoengineer Zirconium Dental Implants.

Zirconium has achieved popularity as a biomaterial for dental and orthopedic implants; however, its bioinertness can compromise implant-tissue integration, especially in compromised patient conditions. More recently, various nanoengineering strategies have been explored to enhance the bioactivity of Ti-based implants; however, nanoengineering of Zr-based implants has not been adequately explored. In this pioneering attempt, we report on the optimized fabrication of various nanostructures on microrough Zr surfaces and explore the influence of the underlying surface topography. In-depth optimization of electrochemical anodization (EA) is performed by tuning various parameters, including substrate topography, voltage/current and time, onto microrough (micromachined) and extremely rough Zr substrates, which represent clinically relevant implant surfaces. Variations of EA factors yielded various nanotopographies, including nanotubes, nanograss and nanotemplates, offering different topographical and chemical combinations. EA optimization and precise current-voltage recording was performed to arrive at clinically translatable and reproducible nanostructures on Zr surfaces. This study will pave the way toward the fabrication of the next generation of nanoengineered Zr-based orthopedic and dental implants.

Towards Clinical Translation: Optimized Fabrication of Controlled Nanostructures on Implant-Relevant Curved Zirconium Surfaces.

Anodization enables fabrication of controlled nanotopographies on Ti implants to offer tailorable bioactivity and local therapy. However, anodization of Zr implants to fabricate ZrO2 nanostructures remains underexplored and are limited to the modification of easy-to-manage flat Zr foils, which do not represent the shape of clinically used implants. In this pioneering study, we report extensive optimization of various nanostructures on implant-relevant micro-rough Zr curved surfaces, bringing this technology closer to clinical translation. Further, we explore the use of sonication to remove the top nanoporous layer to reveal the underlying nanotubes. Nano-engineered Zr surfaces can be applied towards enhancing the bioactivity and therapeutic potential of conventional Zr-based implants.