1.1.1 The Need for Better Dental Implants

An interdisciplinary approach including surface chemistry, physics, and engineering as well as biomechanics is required to develop successful dental implants [1]. Dental implants have been prevalent throughout the past century; however, evidence of dental implants within ancient Mayan and Egyptian civilizations has been found [2]. This brings us to the first prototype of the modern dental implant, which was created by Greenfield in 1913 and was first described as an implant/prosthetic combination made of an iridium–platinum alloy [2]. In the 1970s, Brånemark’s experimentation led to the general acceptance of oral implants and highlighted the importance of osseointegration [3]. We now understand that the success of a dental implant depends on the chemical, physical, mechanical, and topographic characteristics of its surface [4]. As a result of continuous modifications to implant design and surface topography, dental implant placement is a fairly common treatment procedure with high implant survival rates and limited peri‐implant bone loss [5]. In fact, the survival rate of dental implants has been reported to be above 90% [6]. Nowadays, implant surface modifications focus on stronger and faster bone healing to further limit dental implant failure [5]. Even with great advancements in the field of dental implantology, there is still a relatively significant number of dental implant failures, many of which are caused by compromised bone conditions that promote implant failure. For example, diabetes, osteoporosis, obesity, and the use of drugs can decrease bone healing around dental implants [6]. Furthermore, complications involving osseointegrated dental implants can arise from inflammatory conditions associated with bacteria, more specifically, peri‐implantitis [7].

Peri‐implantitis is a pathological condition that occurs in tissues surrounding dental implants [7]. It is characterized by inflammation of the peri‐implant connective tissues as well as loss of supporting bone [7]. In other words, plaque and its byproducts lead to hard and soft tissue breakdown and eventually implant failure, which is a prevalent issue [8]. Factors such as smoking or a history of periodontal disease increase the prevalence of peri‐implantitis [8]. However, even with the lack of the aforementioned factors, features such as implant placement, material biocompatibility, and material degradation also play important roles in the development of peri‐implantitis or osseointegration breakdown [8]. Osseointegration is the formation of bone tissue around the implant without fibrous tissue growth at the bone–implant interface, resulting in direct anchorage of the implant [1]. The osseointegration process can be visualized in Figure 1.1. In fact, the structural and functional union of the implant and living bone is significantly influenced by the surface characteristics of the dental implant [4]. Thus, proper osseointegration is crucial for the success of the implant and is a research topic of great importance. Presently, researchers are finding ways to optimize implant surfaces by studying specific features such as roughness of the implant surface as well as various materials for dental implants in order to promote proper osseointegration and combat peri‐implantitis [10].

Currently, titanium or titanium alloys are the gold standard in dental applications [10]. Most dental implants marketed in the United States are made from either commercially pure titanium (cpTi) or titanium alloys [e.g. Ti6Al4V (TAV)] [4]. Seconds after titanium (Ti) is machined, adsorbed oxygen molecules form a thin oxide layer, which is what body tissues interact with [11]. This oxide layer allows for biocompatibility, while the rest of the implant material plays a role in the implant’s mechanical properties [11]. Chemical processes that occur at the tissue–implant interface include corrosion, adsorption of some biomolecules, denaturing of proteins, and catalytic activity [11]. For instance, TAV implants degrade and result in peri‐implant bone loss [12]. The origins of this degradation were revealed by Chen et al. [12] whose results suggest that the observed bone loss is caused by crevice corrosion and the release of consequential by‐products. These types of issues are driving scientists to find materials and methods to improve dental implants, specifically, the surface of dental implants.

1.1.2 Various Approaches and Biomaterials to Improve Dental Implants

The material composition and surface topography of implants greatly influence the wound healing processes that follow implantation and thus also influence subsequent osseointegration [13]. It has been found that implants with a rough surface allow for better osseointegration; however, excessive roughness can increase the risk of peri‐implantitis and ionic leakage [14]. Thus several methods have been proposed to produce a moderate roughness of 1–2 μm including titanium plasma spraying, particle blasting and acid etching, anodization of the implant surface, and coatings [14]. Examples of these methods are highlighted in Figure 1.2. One method, anodization or anodic oxidation on Ti‐based implants, creates an adherent oxide coating that can have a wide range of stoichiometries as well as microporosities and nanoporosities depending on electrolyte selection and condition manipulation [15].

Biomaterials of interest that could be used as a coating or as a Ti implant replacement include hydroxyapatite (HA), ceramic materials [e.g. alumina, calcium phosphate (CP), and zirconia], nanoparticulate zinc oxide (nZnO), and polyetheretherketone (PEEK). Each of these materials has their own promising aspects. Some studies have reported benefits of using HA‐coated dental implants as well as risks including dissolution of the coating (although they have not shown that dissolution leads to implant loss) [16]. Furthermore, HA coatings may be more susceptible to bacteria as compared to titanium implants [16]. Nevertheless, coating dental implants with HA has helped metallic materials to osseointegrate with the local tissue environment and distribute load stress [17]. Zirconia is a possible alternative to the traditional Ti‐based implant systems as it has superior biological, aesthetic, mechanical, and optical properties [18]. However, more long‐term and comparative clinical trials are necessary in order to validate zirconia as a viable alternative to titanium implants [18].

There are many other dental implant biomaterials that clinicians may not be familiar with. For example, bioactive dental glass‐ceramics (BDGCs) have shown bone–tooth bonding capabilities as well as positive biological reactions at the material–tissue interface [19]. This makes them an attractive implant coating biomaterial. Nanoparticulate zinc oxide is of great interest because of its integration with antimicrobial nanoparticles (NPs) resulting in a coating material that is antibacterial and promotes osteoblast growth, which would help prevent implant failure from aseptic loosening and infection [20]. PEEK possesses excellent mechanical characteristics and may be used in dentistry with surface modification to enhance its osseointegrative characteristics [10]. Another interesting approach to modifying dental implants is using functionally graded materials (FGMs). FGMs are heterogeneous composite materials that have a compositional gradient with continuously varying properties in the thickness direction [21]. Ultimately, these more “novel” biomaterials must be researched in more depth if they are to be used more frequently in the clinic.

An important aspect of biomaterials for dental implants is the stabilization of dental implants with materials such as bioceramic granules and cements. Occasionally, when an implant is placed, there is not enough bone surrounding it [22]. This issue is solved by using bioceramics to fill in the implant–bone gap; however, these materials have poor mechanical properties and cannot stabilize the implant well [22]. Furthermore, it is important to consider the biological interactions that dental cement composition has as it plays significant roles in the host cellular response and the degree of surface degradation from bacterial attack [23]. A group of materials that are of great interest as they can be used as bone substitutes or even as implant‐coating materials are calcium phosphate cements (CPCs) [24, 25]. More specifically, CPCs can be used as alternatives/complements to autogenous bone grafting in implant dentistry as well as coating materials to enhance the osteoinductivity of Ti implants [25]. CPCs can carry growth factors and are also scaffolds for cell proliferation, differentiation, and penetration [25]. Surprisingly, even though the mechanical strength of CPCs is generally low, this is not a critical issue when used for bone repair [24]. Schickert et al. developed CPC reinforced with fibers which improved flexural strength and toughness and, when molded into the implant–bone gap, stabilized the implants, and allowed for a direct connection between the implant and bone [22]. Overall, strategies using materials containing calcium phosphates (CaPs) aim to enhance dental implant osseointegration in the context of immediate loading and to alter the formation of surrounding bone to allow for long‐term success [25].

1.1.3 Working at the Nanoscale to Improve Dental Implants

Another possible approach to altering dental implants is utilizing nanoscale materials. Nanoscale materials take into account that tissue responses are usually dictated by processes that occur at the nanoscale, so by controlling interfacial reactions at the nano level, we can develop new implant surfaces that eliminate rejection while promoting adhesion and integration with the surrounding tissue environment [15]. The effects of nanoscale features are demonstrated in Figure 1.3. An example of this type of nanoscale engineering is using peptides that are bioactive motifs as coatings. For example, the arginine–glycine–aspartate (RGD) peptide is a cell‐adhesive sequence and has been shown to improve the adherence of human gingival fibroblasts and epithelial cells to Ti dental implants [27]. Zhao et al. grafted the bioactive RGD peptide on cpTi and showed that more fibroblasts and epithelial cells adhered onto the RGD‐grafted titanium as compared to CP titanium [27]. Furthermore, Raphel et al. designed an elastin‐like protein (ELP) that includes an extended RGD sequence, and they found that ELP coatings withstand surgical implantation and promote rapid osseointegration [28]. This allows for earlier implant loading and may prevent micromotion that could lead to aseptic loosening and implant failure [28].

Another example of working at the nanoscale is nanopatterned surfaces. In vitro and in vivo studies have shown that nanoscale topographies on titanium surfaces promote cell adhesion, osteogenic differentiation, and bone formation [29]. Shiozawa et al. created smaller, standardized, and controlled nanosized structures on titanium surfaces, providing a design basis for effective nanostructures that optimize the osseointegration of dental implants [29]. Additionally, they observed directional cell growth for some line and groove patterns, and they found that the grain structure controls the cell proliferation rate [29]. Researchers are also using NPs or nanofiber reinforcements in polymer matrices to manipulate the mechanical properties of biomaterials. One application is the use of tetracycline (TCH)‐incorporated polymer nanofibers as a potential antimicrobial surface modifier and osteogenic inducer for Ti dental implants [30]. In fact, Shahi et al. found that there was complete inhibition of biofilm formation by peri‐implantitis‐associated pathogens on fibers containing TCH at 10 and 25 wt% [31].

Besides nanofibers, researchers are also studying nanotubes (NTs) to advance dental implant technology. Carbon nanotubes (CNTs) have a unique structure made of rolled graphene sheets that enhances the shear, compression, and tensile strain resistance of dental implants and are also biocompatible [32]. CNTs have been applied to Ti and zirconia implants as well as with HA nanocomposites [32]. CNT nanocomposite materials have great potential in supporting the weaknesses of current commercial dental implant materials, but there still have some challenges to overcome such as controlling the surface properties of CNTs [32]. One example of a CNT application is the development of a multi‐walled carbon nanotubes‐hydroxyapatite (MWCNTs‐HA) nanocomposite. Park et al. produced MWCNTs‐HA nanocomposites with various MWCNT concentrations which coated Ti surfaces [33]. They showed that HA NPs bonded to the surface of the MWCNTs, and cell tests showed that cell proliferation increased regardless of the MWCNT concentration [33]. Furthermore, the filopodia of cells developed in the presence of MWCNTs, and cytodifferentiation was greatest on the 0.5 wt% MWCNTs‐HA surface. Another type of NT is titanium dioxide (TiO₂) NTs. Zhao et al. modified the surface of Ti substrates by doping TiO₂ NTs on the Ti surface with silicon (Si) [34]. They compared TiO₂ NTs and Ti alone with the Si‐doped TiO₂ NTs and found that the Si‐doped TiO₂ NTs significantly enhanced gene expression for osteogenic differentiation in mouse pre‐osteoblastic cells as well as mineral matrix deposition [34]. Furthermore, in vivo studies of Zhao et al. showed improved implant fixation strength with the use of Si‐doped TiO₂ NTs [34]. From these findings, it is clear that Si‐doped TiO₂ NTs promote osteogenic differentiation of osteoblastic cells and improve bone–Ti integration, which may have a large impact on Ti implant surface modification [34].

Overall, dental implants are commonplace and improve the quality of life for many patients. However, some implants do fail as a result of several possible reasons such as peri‐implantitis, lack of osseointegration, and mechanical shortcomings. Therefore, it is important to develop biomaterials that will promote osseointegration, fend off infection, and stand up to mechanical forces to decrease the chance of dental implant failure. In this review, I will further explore the wide range and recent advances of biomaterials developed to improve dental implants from novel implant materials to nanoscale strategies.

1.2.1 Zirconia

Zirconia implants are made from the strong transition metal zirconium, and zirconia is the oxide form of zirconium [18]. Even though titanium implants have shown long‐term reliability, some disadvantages of this material are allergies or sensitivity to titanium, gingival shrinkage and translucency, and the electrical conductivity and corrosive properties of titanium [36]. Lately, there has been an increase in demand for zirconia‐based implants for aesthetic reasons, but zirconia‐based implants also have a superior soft‐tissue response, are biocompatible, and have comparable osseointegration to traditional titanium implants [18]. Even though zirconia is biocompatible, it is also bioinert meaning that osseointegration can be comprised since bone cannot naturally grow on zirconia surfaces [37]. Thus, it is important to study how surface modifications of zirconia dental implants can promote osseointegration. There are two main approaches to improving the surface properties of implant materials: optimizing roughness and applying a bioactive coating [38]. Furthermore, many physiochemical methods have been used to modify the surface of zirconia‐based implants including acid etching, gritblasting, laser treatment, ultra violet (UV) light, CVD, and PVD [39]. Additionally, coatings such as those made of silica, magnesium, graphene, dopamine, and bioactive molecules have been developed [39]. It is necessary to conduct more long‐term studies on zirconia implants in order to validate these good characteristics so that they may be used more frequently in the clinic [40].

1.2.1.3 Using Nanotechnology to Modify Zirconia‐Based Implants

With the increasing interest in nanotechnology, new materials and methods have been developed that aid in the osseointegration of dental implants. We can appreciate the importance of nano interactions by examining Figure 1.4. Proteins and cell membrane receptors fall within the nanoscale; thus, surface nanoscale roughness plays crucial roles in osteoblast differentiation and tissue regeneration [43].

Typically, Ti implants are modified at the nano level, while zirconia implants are modified using subtractive methods such as sandblasting and acid etching, but now there is much interest in modifying ceramic implant surfaces at the nanoscale level [44]. Generally, research focus is on either modifying zirconia implants by patterning the implant surface or by applying novel ceramic coatings [44]. One idea that takes advantage of nanoscale interactions is mimicking the surface topography of extracellular matrix (ECM) components [44]. This may allow implant surfaces to be more conducive to recruiting bone‐forming cells and therefore new bone formation since ECM components are nanosized by nature and influence tissue response [44]. Another example is anodizing the zirconia surface to form a nanostructured surface filled with NTs that can be loaded with different compounds or drugs that can speed up osseointegration or perhaps even be loaded with antibacterial factors [44]. Forming NTs in zirconia is technically challenging, but from this, we can tell that research is geared toward matching surface treatments between titanium and zirconia [44].

A continuous theme is the importance of osseointegration for successful implants. Thus, it follows that research has been conducted concerning roughening of zirconia implants to promote successful osseointegration at the nanoscale. Rezaei et al. investigated the biological and bone integration capabilities of a zirconia surface with distinct mesoscale, microscale, and nanoscale morphology [45]. They found that the unique hierarchical morphology of the rough zirconia surface showed an increase in osseointegration and accelerated osteoblast differentiation as compared to machine‐smooth zirconia [45]. Interestingly, while cell attachment and proliferation were compromised on rough titanium, these events were not compromised on the rough zirconia surface [45]. Overall, this study provides an effective strategy to improve zirconia implants [45]. Furthermore, these findings demonstrate how we can apply ideas typically used to study and improve Ti implants to zirconia implants.

1.2.2 Hydroxyapatite

HA is a calcium‐phosphate‐based ceramic material that can be found in nature such as in bovine bones, fish bones, oyster shells, and corals but can also be synthesized in the lab [46]. HA is biocompatible and osteophilic and easily incorporates into bone tissues [46]. In fact, HA has been used to replace and augment bone tissues for many years as it plays a large role in the inorganic phase in teeth [46]. Furthermore, HA has been used as a bioactive implant coating to improve osseointegration [47]. It has the capacity to absorb proteins, improve osteoblast proliferation, enhance bone formation, and reduce bone loss, all of which allow for a more rapid fixation and stronger bonding between the implant and host bone [47]. More specifically, these properties allow for uniform bone ingrowth at the bone–implant interface, and as a coating, HA limits fibrous membrane formation and can convert a motion‐induced fibrous membrane into a bony anchorage [47]. Creative applications of HA are currently under investigation. For example, hydroxyapatite nanorods have been grafted onto titanium disk implants to improve strong interactions between implants and teeth [48]. HA does not necessarily have to act as a “stand‐alone” dental implant coating; it can be combined with other materials. For instance, a micro‐nanostructured HA coating was prepared on a titanium surface and then chitosan (CS), an antibacterial agent, was loaded onto the HA surface [49]. This HA/CS composite coating demonstrated improved biological and antibacterial properties, showing promise as a material for dental implants [49]. HA is a tried‐and‐true biomaterial that can help improve existing dental implants and be utilized in novel applications.