Titanium Coatings and Surface Modifications: Toward Clinically Useful

Review pubs.acs.org/journal/abseba

Titanium Coatings and Surface Modifications: Toward Clinically Useful Bioactive Implants Ana Civantos,†,‡ Enrique Martínez-Campos,†,‡ Viviana Ramos,†,§ Carlos Elvira,‡ Alberto Gallardo,*,‡ and Ander Abarrategi*,∥ †

Tissue Engineering Group, Institute of Biofunctional Studies, Associated Unit to the Institute of Polymer Science and Technology (CSIC), Pharmacy Faculty, Complutense University of Madrid (UCM), Paseo Juan XXIII 1, 28040 Madrid, Spain ‡ Polymer Functionalization Group, Institute of Polymer Science and Technology, ICTP-CSIC, Juan de la Cierva, 3, 28006 Madrid, Spain § Noricum S.L., San Sebastián de los Reyes, Av. Fuente Nueva, 14, 28703 Madrid, Spain ∥ Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, U.K. ABSTRACT: Titanium (Ti) is broadly used for clinical purposes in various medical fields related to bone repair because of its favorable mechanical properties and its ability to osseointegrate in host bone tissue. Nowadays, Ti surfaces can be functionalized in order to provide potentially beneficial additional properties. In this review, we summarize different surface modifications of Ti implants, focusing on biological relevance and the biological issues targeted by each specific approach. We first define the historical relevance of Ti as an implantable material, the osseointegration process, and the main complications related to it before describing the biological rationale which motivates Ti surface modification in implantable devices. Then, we explore a variety of physical and chemical modifications feasible on Ti surfaces. Thereafter, we focus on inorganic and organic coatings being developed for implantable Ti devices that are currently under investigation. Finally, we summarize the surface-modification approaches clinically available or undergoing clinical trials. KEYWORDS: titanium, coatings, bone, implants, tissue engineering, osseointegration

1. INTRODUCTION 1.1. Historical Perspective of Ti as a Bone Implantable Material. For many decades, materials science and implantology researchers have been looking for improvements in the design of devices useful for clinical applications in body part replacement. Bone has been one of the main target-tissues in this field because of its specific properties and the possibility to tackle its functional repair using rigid biocompatible implants and surgical techniques. Currently, titanium (Ti) is the standard material for many implants designed for dental and orthopedic applications. One of the prerequisites for successful orthopedic implants is that they exhibit mechanical properties similar to natural bone tissue, and in this sense, the modulus and hardness properties of titanium (Ti) are close to that of cortical bone tissue, making it a good material for the intended purpose. The first reports of Ti being applied for implant fabrication date back to the late 1930s, after demonstrating better behavior than stainless steel and cobalt alloys.1 Titanium and its alloys (mainly mixed with aluminum or vanadium) were first introduced into surgeries in the 1950s, after being applied in dentistry for the previous decade. Beyond dentistry applications in implants, crowns, bridges, or other prosthesis,2 there are well-documented Ti © 2017 American Chemical Society

applications in hip and other joint replacement surgeries (such as shoulder, elbow, or knee) or spinal fixation devices.3 Indeed, Ti is also used in cardiovascular stents. In these interventions, commercially pure Ti (Ti CP) and extra low interstitial Ti-6Al4 V (ELI) are the ones most commonly used for implant fabrication.1 In recent decades, the favorable biocompatibility and corrosion resistance of Ti-based materials, two essential features for an implantable metal device, has been proven in many experimental and clinical investigations. Metallic materials, such as Ti, also offer the mechanical strength and resilience that is required to successfully simulate bone tissue. Titanium implants display remarkable behavior in terms of load-bearing support, due to titanium’s excellent mechanical performance (maximum load, bending, and fatigue strength).4 Additionally, specific mechanical properties associated with Ti implants, such as stiffness, also positively regulate bone cell phenotypic specification.5 Special Issue: Biomimetic Bioactive Biomaterials: The Next Generation of Implantable Devices Received: September 30, 2016 Accepted: February 28, 2017 Published: February 28, 2017 1245

DOI: 10.1021/acsbiomaterials.6b00604 ACS Biomater. Sci. Eng. 2017, 3, 1245−1261

Review

ACS Biomaterials Science & Engineering 1.2. Osseointegration and Immune System Response in Ti Implants. Despite its remarkable success as a bone tissue implant-material, decades of experience in Ti implantation have highlighted some aspects that need to be improved. Osseointegration has been defined as a key factor for implant success and can be defined as a direct structural and functional connection between ordered, living bone and the surface of a load carrying implant6 (Figure 1). Classic approaches included

cellular interactions between implanted devices and the surrounding tissues are essential to bone implant success or failure. Bone homeostasis can be unbalanced by implant treatment after an injury or other pathologies. Despite its historical consideration as an inert material, Ti implants may induce a soft foreign body response as it is made of nonbiological components (Figure 2), which may lead to eventual implant rejection. After initial blood interaction with an implant surface, an immune system response is triggered, with macrophage specific polarization to M1 or M2 phenotypes depending on several factors, like biomaterial surface properties or the presence of specific microbial infectious agents. Consequently, Ti devices may be recognized as foreign bodies and surrounded by granulation tissue. In that scenario, a subsequent immune system response is needed to avoid chronic inflammation and fibrosis and to initiate tissue remodeling for implant integration.1,8 Otherwise, the Ti implant may fail, a process largely related to the development of strong and enduring fibrotic tissue that prevents bone cell colonization and isolates the implant from host tissue. 1.3. Ti Surfaces and Target Modifications to Improve Implantable Devices. Titanium and its alloys are defined as inert materials. Although this property was historically considered desirable, inert Ti is hardly capable of battling infections nor actively regulating specific bone cell processes, properties which are desirable for bone healing implants. Therefore, research efforts have been focused on the improvement of Ti surfaces to address at least one, if not both, of these two issues. As a consequence, a variety of Ti surface modifications and coating approaches now exist that can directly trigger bone formation or even reduce the risk of infections.4 Most Ti coatings follow a biological rationale and aim to mimic the bone tissue and its components. For example, bone tissue is composed of an organic part (collagenous matrix) and an inorganic component (calcium phosphate nanocrystals),4b and therefore both organic and inorganic related systems have been the preferred materials for Ti coating purposes. Moreover, molecules that directly regulate osteogenic

Figure 1. Osseointegration. Histological images of rabbit tibia bonetissue harvested 8 weeks post-screw-implantation surgery. The Ti screw can be observed as black-opaque, while bone can be observed as the red tissue. (A) Implant osseointegrated with direct contact between host bones and implant surface. (B) Nonintegrated implant with lack of direct bone−implant contact.

fibro-osseous integration as a valid strategy to consider a dental implant successful.7 In this model, a fibrous collagen tissue surrounds the implant during healing, avoiding bone tissue contact. However, despite the initial promise, long-term dental implants based on this strategy tended to fail. Apart from fibrous tissue formation, implant failure has been also associated with several other causes, such as infections in the implanted area, mechanical loosening and bone resorption, among others. Considering this, it is clear that molecular and

Figure 2. Titanium implantation and biological response. After surgery, serum proteins adsorb onto the titanium surface, modulating immune system activity. In this context, neutrophiles, lymphocytes, monocytes, and finally macrophages play a crucial role in recognizing material surface characteristics and expressing biological factors in the surrounding tissue. These signals polarize the macrophage population to M1 (proinflammatory phenotype, usually associated with microbial infections) or to M2 (anti-inflammatory phenotype). After this polarization, fibrous encapsulation of the biomaterial could occur as a consequence of a foreign body response. Both events affect future implant integration in bone tissue, with three possible scenarios. (A) Failure. Macrophage M1 polarization and fibrous tissue encapsulation (top image) led to foreign body giant cell (FBGC) formation, tissue inflammation, and implant rejection. (B,C) Integration. (B) The biomaterial is surrounded by granulation tissue, but M2 macrophage-phenotype is predominant, which causes a progressive transformation of the granulation tissue into bone tissue after matrix deposition. (C) The M2 macrophage-phenotype is present, and there is no adverse reaction, favoring osseointegration and implantation success. 1246


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Sa: surface area roughness. Ra: profile roughness. BIC: bone-to-implant contact.

Electrochemical modification to increase the thickness of the TiO2 layer. Several techniques and electrolytic solutions are used to achieve titanium oxidation. In anodic oxidation, the implant is exposed to an electric circuit with the implant serving as an anode.15 Plasma electrolytic oxidation (PEO) includes higher voltages and could generate crystalline coatings. Usually produces porous micro- or nanostructures (with pore sizes from submicron −0.4 μm- to several microns) and moderate degrees of surface roughness (Sa = 0.9 μm; TiUnite).26

oxidation methods: anodizing

a

Photofunctionalization using UV light alters titanium dioxide distribution on the surface, reduces the degree of surface hydrocarbon, and increases surface energy and wettability.23,24

Some treatments reach several levels of microtopography (Sa = 1 μm). Roughness and porosity can increase to the micro- and nanoscale.15 Combined with other methods (sandblasting and/or peroxidation), it can also impart nanofeatures to the surface and remove contaminants.19 Spraying thermally melted Ti on the implant substrate. Increase of surface roughness to Ra = 4−5 μm.13 Laser micromachining generates a pattern of micro- and nanoscale microchannels (Laser Lok; 8 μm) around the implant collar.15,22

Frequently used in combination with etching to finish the process, as in the case for commercially available dental implants. Acid-etching treatments are generally performed at high temperatures using acids (hydrofluoric, hydrochloric, nitric, or sulfuric acid or a combination of them referred to as dual acid etching) with proper neutralizing techniques.16a

UV treatment

laser ablation

Ti plasma spray

etching

Bombardment of implant surfaces with particles (sand, grits, powder, etc.) of diverse composition (sand, aluminum oxide, titanium oxide, etc. or a combination of them). Roughness achieved (Ra values from 0.5 to 6 μm) depends on the blasting media, size, and shape of the particles, and other features (pressure, distance, etc.).16

blasting

description

Turned, milled, or polished manufacturing process. Increase of material surface area and roughness, reaching surface topographical value of Sa = 0.9.13

machining

type of modification

Table 1. Physico/Chemical Surface Modifications over the Ti Surfacea biological effect

In vivo: Improved integration of dental implants in the surrounding tissue. Microchannels act as a biologic seal by eliciting the attachment of connective tissue and inhibiting epithelial downgrowth.22 In vitro: UV treatment raises the level of protein absorption and cellular attachment to the implant surface.15 In vivo: In animal surgeries, it accelerates bone formation particularly in early phases of osseointegration.25 In vitro: enhanced protein adsorption, biocompatibility, and other mechanical properties (biocorrosion).27 Augmented in vitro cell adhesion, proliferation, and extracellular matrix deposition of human gingival fibroblasts.28 In vivo: augmented BIC and osteoconductive capacity in animal studies.26b

In vivo: High osseointegration20 and good removal torque values21 in animal studies.

In vitro and in vivo: increased in vitro and in vivo cell adhesion and bone formation, enhancing osseointegration and bone ingrowth.16a In addition, nanotopography accelerates other cell processes, like proliferation or differentiation in in vitro experiments.19,15 In vivo: Increased torque rotation force value and BIC in animal surgeries.16a

In vitro: Polishing methods can prevent bacterial or fungal colonization.14 In vivo: Imperfections along machined surfaces enable osteogenic cells to attach and to deposit bone. Improvement at the bone-to-implant interface.15 Roughness increase in the microscale affects cell attachment and tissue ingrowth. In vitro: the blasting technique can also modulate in vitro bacterial adhesion.17 In vivo: improvement in osteogenesis and bone-to implant contact.18

ACS Biomaterials Science & Engineering Review


Review

ACS Biomaterials Science & Engineering differentiation processes, such as certain extracellular matrix (ECM) proteins and growth factors (GFs), have been thoroughly tested in combination with coating materials and incorporated into them using different approaches,9 in order to induce bone formation and improve implant osseointegration. Similarly, antibiotics and bactericide agents have been incorporated into implant-coatings, with a view to reducing and preventing infections associated with implantation processes. In this review, we summarize several different approaches in Ti surface modifications and coatings. Specifically, we start with modifications performed on titanium surfaces, and then we describe specific organic and inorganic coatings. Each approach is introduced, the intended uses are discussed, and the pros and cons of each strategy are highlighted, with special focus on the biological context and the possible incorporation of biomolecule carriers. Finally, we introduce and discuss some of the approaches already tested in clinical settings. In this text, we tried to cover the last two decades of relevant scientific findings in the mentioned research areas. For this aim, bibliography was selected based on the expertise of the authors, keywords, and relevance of the works in each one of the sections covered.

2. PHYSICAL/CHEMICAL TI SURFACE MODIFICATIONS Certain topographic characteristics of Ti implants, such as porosity or roughness, directly affect the progression of cell adhesion, proliferation, and differentiation.10 Additionally, increased surface area promotes cell attachment and augments biomechanical interlocking between bone tissue and an implant.4b For decades, surface topography modification was based on machining processes, with turned implants being the most commercially successful design.11 Since then, several physical and chemical techniques capable of modifying the Ti surface topography, such as Ti plasma spraying, grift-blasting, acid etching, or plasma electrolytic oxidation, have been applied to Ti implants in order to enhance surface features12 (Table 1). These techniques modify surface roughness (Figure 3) or induce the formation of a Ti oxide layer, thereby improving tissue response. In the following sections, we introduce both concepts. 2.1. Ti Surface Roughness as a Target. There is a consensus that surface roughening enhances in vivo bone integration and therefore implant stability.29 Similarly, it is known that surface pores interact with bone cell populations, which are reactive to pore size, pore shape, or interconnectivity.4b The most conventional techniques induce the formation of microscale porosity on Ti surfaces (Table 1), while more recently the relevance of nanoscale surface patterns has been also explored. Focused on microgrooved surfaces, animal surgeries have shown the good performance of micropatterned Ti surfaces in terms of improving bone integration.30 It is considered that physical and chemical properties inside the grooves may be different from the outside surface, which may directly affect cell adhesion and proliferation. The phenomenon of contact guidance, which is cell growth aligned along the microgrooves, can have direct applications in in vitro tissue engineering but also improve in vivo behavior.31 Additionally, to improve antibiofouling properties, while simultaneously maintaining mammalian cell cytocompatibility, mixed strategies can be applied using antimicrobial peptides to avoid bacterial or fungal

Figure 3. Surface treatment. Gross appearance and surface electron microscopy (SEM) images showing micrometric surface structure of (A) machined, turned implant and (B) sand-blasted and then acidetched implant. Note the differences in surface roughness at the micrometric level.

infections in addition to the micropatterning of the surfaces. As an example, the antimicrobial peptide GL13K (GKIIKLKASLKLL-NH2) modified microgroove Ti surfaces improved cytocompatibility compared to smooth surfaces, and antibacterial activity was simultaneously conserved.31 Neovascularization in the peri-implant bone area, which is another necessary requirement for implant success, is a biological process that can be stimulated by specific Ti surface microtopography, which modulates secretion of angiogenic growth factors by osteoblasts.32 Focusing on nanoscale roughness, nanotechnology is increasingly being employed in advanced implant design. Texture modulation at a nanoscale level can directly affect cell recognition, adhesion, and proliferation and may modify osteogenic events.33 Moreover, specific cell adhesion selectivity34 or bacterial proliferation35 can be regulated on nanoscale topographies. The techniques that can achieve precise nanoscale modification in dental Ti implants are usually applied to previously microtextured surfaces. One method that has been applied to achieve nanoscale texturing on Ti implants is hydrofluoric acid etching. These nanopatterned Ti implants have demonstrated improved in vitro behavior in comparison to similar micropatterned counterparts, up-regulating osteogenic marker expression.36 Notably, for some nanostructured dental implants tested in animal surgeries, some properties such as biomechanical fixation37 or bone-to-implant contact38 did not show clear differences between micro- and nanotextured groups. Therefore, proper controls, long-term studies, or complementary molecular analysis are still required to confirm the efficacy of nanostructuration and microscaled surfacetreated dental implants. 1248


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ACS Biomaterials Science & Engineering

Figure 4. Simplified schematic of some ceramic-deposition techniques. (A) Plasma-spraying involves the use of a plasma flame. The technique results in the formation of an oxide film on the Ti surface and allows ceramic coating formation by heating and propelling hydroxyapatite onto the Ti surface. (B,C) Techniques involving the immersion of implants to achieve a ceramic coating. (B) Schematic for dipping, sol−gel, and biomimetic coating techniques. Dipping the Ti material into the coating solution facilitates the formation of a wet layer, which is then dried from solvent and further treated with high-temperature processes to form a ceramic coating. Similarly, the sol−gel technique involves the application of a wet gel onto the target material, requiring further drying of the solvent to form a xerogel and a final high-temperature treatment to form a dense ceramic layer. Biomimetic coating of Ti can also be achieved by using body plasma or simulated body fluids which induce the oxidation of the Ti surface and the precipitation of amorphous calcium crystals. (C) Electrophoretic deposition involves the use of two electrodes to induce the migration of particles in solution toward the surface to be coated. The particles deposited on the surface of the Ti are then fused at high temperatures to form an inorganic coating.

Other favorable characteristics in the oxide layer, like antibacterial behavior, can be obtained through light excitation, without sacrificing its mammalian cell cytocompatibility.41 There are several approaches analyzing Ti oxide ability in killing bacteria, a consequence of its catalytic properties under photoirradiation. After photon absorption, electron−hole pairs are created in material surface and could react directly with bacterial membrane lipids or indirectly produce hydroxyl radicals. Using strong enough stimuli, such as ultraviolet light irradiation, these ions can produce microbial lysis. Nevertheless, doping with metallic or nonmetallic species can achieve visible light photoactivity of Ti dioxide. Thus, under visible light exposure nitrogen-doped Ti oxide surfaces with palladium oxide nanoparticles also release hydroxyl radicals that perform the oxidative attack in the interior of bacteria cells.41 Because of this selective biological activity, there are other metallic oxide implants that are being developed, like zirconium oxides, with remarkable success in terms of osseointegration.42 As a final note in this section, it is known that Ti surfaces treated with physical or chemical treatments can also present chemical surface alterations that can affect early cell attachment, differentiation, and bone matrix secretion.43 Therefore, when this type of surface-modified Ti implant is tested in biomedical applications, it is hard to discern between improvements due to added physical characteristics or changes in chemical composition. In this sense, it is of note that in physiological conditions spontaneous Ti oxides are also formed. Therefore, modern surface treatments should include this multifactorial perspective in their design in order to predict an optimal cellular response.

Physical and chemical modification procedures developed to modify surface roughness can be combined with finishing treatments, such as polishing methods, which can also influence eukaryotic cell activity and bacterial viability.29b,39 For example, it has been described in dental applications that polishing treatments could have an additional role preventing bacterial or fungal colonization,14 a highly desired feature for the avoidance of peri-implantitis or other pathologies. Nevertheless, there is no general rule to correlate biofilm formation to a specific roughening or polishing level of the metallic surface. In summary, surfaces with moderately textured microtopographies (surface area roughness of 1−2 μm) have demonstrated an improvement in osseointegration over smoother counterparts, accelerating cell processes and shortening healing time.11 At a nanoscale level, there are studies which point to the possible added value of the nanofeatures in in vitro and animal surgery studies, but deeper clinical analysis is still needed to show their distinct advantages over their microscale analogues. 2.2. Ti Oxide Layer as a Ti Surface-Activation Method. Titanium implants are often activated with physical or chemical treatments that actively produce a thin oxide layer. Metal oxide coatings enhance biocompatibility and other favorable properties, such as the biocorrosion resistance of the metallic implants.27 It has been described that exposure to physiological conditions creates a heterogeneous, spontaneous, and polarized Ti oxide surface that promotes preferential adsorption of lipoproteins and glycolipids from serum.40 This protein-coated Ti oxide surface can improve initial interactions with bone cells, simulating the native biological conditions which favors bone tissue growth. Nevertheless, it is necessary to study the correlation between the physicochemical properties of the oxidized surfaces and preferential protein adsorption in order to design or predict biocompatibility improvements.27 The Ti oxide layer can additionally be activated to enhance its behavior in clinical applications. Activation can be achieved by doping with inorganic components, such as Ca, P, Si, or Mg, which are involved in bone metabolism, which can favor bone homeostasis and augment mineralization and angiogenesis.

3. INORGANIC COATINGS: CERAMICS Ceramic coatings have been thoroughly tested on Ti surfaces44 with a view to improving implant-osteointegration.45 Different methods have been developed with this aim, and a high number of implantable products are already clinically available. The literature is extensive,46 and existing ceramic coating methods have been thoroughly summarized elsewhere.45a,46,47 In this review, we will focus on calcium phosphate (CaP) and bioactive 1249


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3.1.1. Molecules to Induce Bone Formation. Focusing on surface adsorption onto ceramics, the reported benefits of the addition of transforming growth factor beta-1 (TGFB-1) onto ceramic surfaces is somewhat controversial in the literature.57 For example, while one study shows TGFB-1 adsorption onto ceramic-coated implants results in increased bone formation related to higher osteoblast proliferation and higher matrix deposition,58 other similar studies show no benefits or only moderate enhancement of bone ingrowth with no benefit in terms of implant fixation.59 TGFB-2 and bone morphogenetic protein 2 (BMP-2) growth factors have also been similarly studied, with reports of moderate benefits.60 Moving on to the biomimetic deposition approach, Wen et al. provided proof-ofconcept by testing the coprecipitation of bovine serum albumin (BSA) and calcium phosphate on Ti,61 while Wernike et al. measured the BSA release kinetics from in vitro cell-seeded materials, confirming cell-dependent BSA delivery.62 Merging both the adsorption and biomimetic techniques, Hunziker et al. demonstrated that BMP-2 could be incorporated into biomimetic coatings and could be combined with surface absorption of the same protein resulting in increased in vivo bone formation and osseointegration of implants in miniature pigs.63 Other authors also incorporated BMP-2 into biomimetic coatings in implants. These were proven to be successful in terms of bone formation in vivo using different animal models, with reported reductions in host inflammatory response.55a,64 Furthermore, other GFs, such as FGF-2, have also been immobilized prompting slow release from implant calcium coatings and the stimulation of osteogenesis in in vivo settings,65 while FGF-2 and the antibiotic antimycin A have been combined for a dual delivery strategy.66 However, a major drawback of GF incorporation into biomimetic coatings is the low protein incorporation rate, a mere 3−15%, which represents a highly expensive waste of bioactive molecules.64a,67 Finally, biomimetic calcium deposition has been thoroughly tested for DNA immobilization and cell transfection, and is summarized elsewhere.68 3.1.2. Molecules to Prevent Bone Resorption. Drugs belonging to the bisphosphonate family are popular candidate drugs capable of inducing osteoclast apoptosis, decreasing bone resorption, and therefore modifying the homeostasis of bone in favor of bone formation, when loaded into ceramic coatings. Bisphosphonates have been incorporated into ceramic coatings using different techniques and were shown to be beneficial for the stimulation of bone formation and for implant osseointegration.69 However, the efficacy of different biphosphonates in promoting implant osseointegration is variable. For example, zoledronic acid (ZOL) in Ti implants was shown to be more effective in an in vivo model than ibandronate or parmidronate in improving peri-implant bone density in osteoporotic rats.70 Because of evidence supporting its effectiveness, ZOL is the most used of the bisphosphonates in Ti coatings, specifically in CaP coatings for dental implants, where it has been proven to increase bone quality, preserving bone volume around Ti implants.71 Moreover, ZOL has also been grafted to HA72 and other polymeric substrates and applied in implant coatings,73 with positive effects in terms of osteoblast activity, inhibiting osteoclast resorption, and inducing fracture healing acceleration. 3.1.3. Molecules with Antibiotic and Immunomodulation Properties. As infections are one of the major causes of implant failure, modern ceramic coating design has been directed to address this issue.74 For instance, the antibiotics vancomycin

glass coatings (Figure 4) and the approaches which implement them with a view to providing additional and favorable implant properties. The biological rationale behind the use of ceramic coatings relies on their biocompatibility and on their ability to improve the bone healing process.48 In general, ceramic coatings are considered osteoconductive; they improve the osseointegration of implanted materials, mimicking the natural process of the bone healing process. To this end, calcium release from ceramic coatings allows for the deposition of a biocompatible thin layer of biological apatite, which facilitates host cells to adhere and differentiate, eventually yielding proper osseointegration of the implanted material.49 Moreover, ceramics have been tested as GF and drug delivery carriers50 with a view to inducing bone formation by stimulating the cells with the same factors present during natural bone healing.9a Biological apatite is a carbonated hydroxyapatite and the main component of bone mineral. Therefore, hydroxyapatite (HA) and other CaP minerals have been applied as the preferred ceramic materials for coating purposes.45a Bioactive glasses are mixtures of oxides, mainly SiO2, CaO, and P2O5 and have also been proposed as coating materials.51 They are called bioactive because they show great adhesion to host bone tissue after bone implantation, behavior largely linked to a rapidly forming biocompatible carbonated apatite surface layer after implantation. Both CaP and bioglass coatings have been thoroughly tested, and there are a number of ASTM standard specifications related to these ceramic coatings for implantable materials, such as F1185, F1926, F1609, and F1160. 3.1. Incorporation of Bioactive Molecules in Ceramic Coatings. As drug delivery carriers, ceramic coatings have been assessed as vehicles for molecules aimed at activating bone formation, avoiding infections, bone resorption, and foreign body reactions or modulating inflammatory reactions. The ceramic coating method used determines the technique to be used in order to incorporate bioactive agents, which roughly could be separated in 2 groups; techniques related to surface adsorption; or techniques related to entrapping the molecule of interest. Many of most common CaP or bioglass coating methods, such as the plasma-spraying technique45a,47a,b,52 or others46,47d,53 (Figure 4), require a high temperature step to form the ceramic coating, and therefore, the further addition of drugs or GFs is usually performed by surface adsorption.9,26a Unfortunately, a side effect of the surface absorption technique is that it yields a burst-type delivery of the loaded bioactive molecule, rather than a controlled and sustained delivery. To overcome this issue, the ceramic surface chemical composition can be modified, and the surface itself may be functionalized with a view to enhancing bioactive molecular binding and to further improve delivery properties.54 On the other hand, body plasma or simulated body fluids have been used to induce the precipitation of amorphous calcium phosphate crystals on oxidized and carboxylate alloy surfaces, a process known as biomimetic deposition or biomimetic coating55 (Figure 4). An advantage of this technique is the possibility to deposit bioactive molecules during the coating formation process, molecules which will be further delivered in a more controlled fashion.55a,56 Here, we summarize some of the approaches reported in the literature. We organize sections according to the property of the incorporated molecule, and then, we take into account the incorporation method used. 1250


Deposition techniques include physical adsorption; wet deposition coatings; electrochemical treatment; and electrospray deposition (ESD).

hydrogel approaches (gel coating and physical deposition)

blood and PRPs

deposition techniques such as physical adsorption; wet deposition coatings such as dip coating and layer-by-layer (LBL); electrochemical treatment and electrospray deposition (ESD)

GAGs and proteoglycans: chondroitin sulfate, heparan sulfate, hyaluronic acid

RGD and peptides

plasma treatment, chemical deposition, matrix-assisted pulsed laser evaporation (MAPLE)

poly(methyl methacrylate) (PMMA)

Deposition techniques include physical adsorption; wet deposition coating such as dip coating and layer-by-layer (LBL); electrochemically assisted deposition method (ECAD); and electrospray deposition (ESD).

plasma treatment, chemical deposition, graft polymerization, pulse laser deposition (PLD)

poly-caprolactone (PCL)

collagen and other ECM proteins: vitronectin, fibronectin, bone sialoprotein

physical and chemical deposition, silanization, electropolymerization, or plasma polymerization

poly ethylene glycol (PEG)

Deposition techniques include physical adsorption; wet deposition coating such as dip coating and layer-by-layer (LBL); electrochemical treatment; and electrospray deposition (ESD).

plasma treatment, polyelectrolyte multilayer (PEM), chemical deposition, graft polymerization

poly lactic-co-glycolic acid (PLGA)

polyssacharides (chitosan)

coating method

coating type

Table 2. Organic Coatings physicochemical and biological coating properties Synthetic biocompatible, biodegradable, nontoxic, inexpensive to apply, environmentally friendly, approved for use in humans, good mechanical properties In vitro: tunable degradation rates, lacks biological cues but increases Ti roughness promoting cell interaction with implant surface and prevents bacterial adhesion and colonization due to its antifouling activity. In vivo: suitable as a control delivery system of GFs improving Ti osseointegration and bone fracture healing.8,74c,84 biocompatible, biodegradable, nontoxic, good mechanical properties (hydrophilic and great filmogenic capacity); antifouling properties In vitro: presents faster degradation rates and low immune response; prevents bacterial adhesion. In vivo: accelerates fracture healing acting as a carrier of GFs.8,74c,84,85 biocompatible, environmentally friendly, and hydrophobic; bioresorbable with slow degradation rates in physiological conditions, with the release of acidic products; no recognition cell sites; approved by the FDA for use in the biomedical field In vitro: facilitates cell adhesion and proliferation, suitable carrier of GFs, increasing cell attachment, proliferation, and cell differentiation. In vivo: improves mechanical resistance with high protection from corrosion.84b,85,86 biocompatible, brittle, good mechanical properties In vitro: lack of biological cues, increases implant roughness, and prevents fibrin detachment and biofilm formation. In vivo: used as bone cement in odontology and used as a composite with titanium oxide.84b,85,86 Natural In vitro: nontoxic and biodegradable, increases the biocompatibility of Ti surfaces, reproducing the bone tissue environment (component of the ECM as GAGs). Poor mechanical properties. Possible functionalization with ECM proteins, polysaccharides, GFs, and adhesion peptides. Supports hydration and protection from free radical-induced inflammation due to the ion scavenging character. In vivo: increases cell attachment, can retain GFs and bioactive molecules, promoting osteoinduction and implant osseointegration.84b,86,87 biodegradable coating, similar structure to GAGs. In vitro: osteoconductive, antibacterial, and chemostactic. Can be functionalized with GFs and adhesion peptides and can form biocomposites with HA. In vitro: reduces biofilm formation and bacterial colonization, good candidates for controlled GF delivery, and promotes cell adhesion and cell differentiation. In vivo: shows hemostatic effects, promotes the vascularization of new bone, and enhances bone tissue ingrowth, wound healing, and Ti osseointegration.87,88 main proteins of ECM, biodegradable, osteogenic, low immune response. Fast degradation and poor mechanical properties, often applied as a biocomposite with ceramics or HA. In vitro: cell-binding properties (contains RGD sequence) increasing cellular adhesion, subsequent proliferation, and cell differentiation. Chemoattractant, retaining GFs and other bioactive molecules. In vivo: promotes osteoinduction and enhances bone tissue regeneration.57,89 Tripeptide and short sequences presented in mainly ECM proteins as cell adhesion sites. In vitro: increases cell interactions between cells and implant surfaces. Frequently used in combination with polymers, ceramics and GFs. In vivo: favors implant osseointegration by promoting osteoblast cell attachment.31,90 complex composition (great variety and variable efficacy); more accurate bone environment reproduction. In vitro: reduces immune response by decreasing the leukocyte population and activating platelet function, releases GFs, and increases angiogenic and chemotactic molecules. In vivo: enhances osteoblastic cell attachment, proliferation, and differentiation due to GF presence and supports a suitable fibrin matrix, increases osteogenic potential, and enhances Ti osseointegration.57,91

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as hydrophilic/hydrophobic balance, functionality, or degradability. The biodegradable properties of some polymers facilitates temporary Ti surface coatings, favoring dynamic tissue remodeling. Ideally, these biodegradable coatings should promote new bone tissue formation and increase osseointegration at the same time as they disappear and degrade to nontoxic byproducts. In terms of functionality, the organic coating may be selected to mimic the natural environment of bone tissue, to trigger a specific biological response, or to face other challenges. In addition, organic coatings may be activated by the physical or chemical incorporation of active compounds, such as bioactive antimicrobial peptides or peptides and GFs (BMP-2, BMP-7), to regulate cell growth and differentiation.4a,8 4.1. Synthetic Coatings. The fabrication and design of synthetic polymer coatings is hugely versatile, and they can be tailored to impart prespecified characteristics, by combining more than one monomer or polymer, including biological agents that influence the surrounding tissues. Such coatings represent a flexible alternative to face common challenges that can occur with biomedical devices implants, such as poor physical properties or immune rejection risks due to bacterial colonization.74c,84b,92 A multitude of synthetic polymeric coatings have been described. Coating parameters such as biocompatibility, biodegradability, or mechanical stability depend on the constituent monomers or polymers. Examples of degradable polymers are poly(D,L-lactic-co-glycolic acid) (PLGA), poly caprolactone (PCL), polyhydroxyalkanoates (PHAs), and polyphosphazenes, with the latter under current clinical stage investigation.84b Hydrophilic biostable polymers such as poly(vinyl alcohol) (PVA), polymethacrylic acid (PMA), or polyethylene glycol (PEG) are frequently used as coatings for metallic implants, offering a soft interface that, in some cases, inhibits bacterial adhesion on Ti based materials.74c In terms of surface topography, some synthetic polymeric coatings could be tailored in order to achieve a semiordered nanoscale surface. Such nanotexturing may serve to improve the cell response, as was reported for the polymethyl methacrylate (PMMA) polymer, which showed superior mesenchymal stem cell differentiation, and enhance the induction of TGFB-1 expression.86 The combination of different polymers, such as synthetic and natural ones, has showed a remarkable increase in the coating topography. In that sense, a stable PVA/natural polymer composite coating developed by Mishra et al. for Ti surfaces imparted improved mechanical properties to the Ti surfaces over uncoated counterparts.92 In addition, this biocomposite coating has been used to encapsulate silver nanoparticles achieving a longterm release of Ag+ which has been previously described for its antibacterial activity. 4.2. Natural Coatings. Naturally occurring coatings are a subset of bioactive materials that can be grouped into three categories: polysaccharides, ECM proteins, and peptides. This increasing interest stems from their inherent low toxicity, biodegradability, low cost, and renewability.74c,84b,92 In addition, natural coatings have shown specific advantages in bone tissue engineering, through the activation of specific biological signaling pathways, induction of cell adhesion, and the modification of bone remodeling.71 From a manufacturing viewpoint, the composition of natural systems is far more complex than synthetic systems. Furthermore, synthetic polymers can be developed and

and angiomicin have been used in combination with ceramic coatings,75 while nanoporous silica coatings have been tested as in vivo delivery systems for antibiotics.76 Alternatively, antimicrobial peptides have been applied to impart both antimicrobial and immunomodulation properties. In this context, the peptides Tet213 and HHC36 have been combined with calcium phosphate coatings with great antibiotic success.77 A different approach has seen silver (Ag) used as a bactericide, and it is frequently used in coatings to reduce and prevent infection associated with postoperative complications in orthopedic surgery. It has shown broad-spectrum efficacy, killing both Gram-negative and Gram-positive bacteria. Its main mechanism of action occurs through the disruption of bacterial membranes where it can bind to enzymes and DNA, thus inactivating metabolic processes and bacterial replication.78 Many studies have shown the beneficial effects of silver-coated substrates, with several examples highlighting its effective antimicrobial potency against Staphylococcus aureus (S. aureus), Staphylococcus epidermidis (S. epidermidis), and Escherichia coli (E. coli), among others.79 The addition of Ag, as ions or nanoparticles on implant surfaces, is a great strategy to hinder biofilm forming bacteria and hence prevent colonization and infection.79a Therefore, silver has been added to HA films with proven antibacterial effects,80 while other compounds such as zinc and copper have also been used with a view to the same end results.81 Very recently, HA coatings were doped with Ag nanoparticles (AgNP) and tested for bactericidal efficacy. The results showed low levels of biofilm formation and lower numbers of S. aureus and E. coli colony clusters compared to those of controls.79a Other authors have evaluated AgNP used in combination with GFs such as BMP-2. Specifically, Xie et al. described a strategy for the dual release of Ag nanoparticles and BMP-2 from HA coatings. These bioactive coatings showed antimicrobial activity against S. epidermidis and E. coli and favored osteoblast cell-spreading and attachment in in vitro conditions.82 Similarly, silver coatings of Ti bars implanted in rabbit femurs resulted in increased osteoconductivity.82 Finally, ceramic coatings have been used not only to improve osseointegration and bone formation but also to mitigate some complications related to Ti implantation procedures.8 For example, metal corrosion could lead to the mechanical failure of an implant, while ceramic coatings have shown anticorrosive properties on metallic surfaces.83

4. ORGANIC COATINGS Organic surface modifications involve the immobilization of different polymers and molecules such as synthetic polymers, polysaccharides, proteins, GFs, or peptides onto biomaterial surfaces to target cell response at the tissue−implant interface4b (Table 2). Although some of these coatings may hinder osteoblast function on the implant surface, these organic coatings may mimic the surrounding biological environment in terms of components (some ECM polymers or active peptides have been used), water content, or mechanical properties. The modulus and hardness properties of Ti are close to those of cortical bone tissue but are far from those of trabecular biological bone or cartilage tissue. In this sense, organic polymers have been extensively studied as Ti coatings, providing improvements on surface properties for the intended use.8,84b,92 Organic coatings, especially polymers (natural or synthetic), are highly versatile and flexible structures that can be tailored, to some extent, to adjust property influencing parameters such 1252


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Figure 5. Chitosan coating on a Ti dental implant. (A) HCl acid etching and silica sandblasting a double treated Ti surface. (B) The same surface coated with a chitosan film. (C) Discontinuity detail in the coating (see arrow in B) highlighting the thickness of the applied coating (see arrows in C).

improve the biocompatibility and mechanical properties of Ti samples. In vitro studies have shown that the presence of these combined polymeric coatings have resulted in increased cell proliferation, higher quantities of collagen type I, and upregulation of bone markers such ALP.98 Chitosan coated on pure Ti surfaces has been studied indepth.88a−c,99 In in vitro experiments, the presence of a chitosan coating has been reported to promote serum protein adsorption, cell proliferation, and osteoblast cell differentiation.99a Moreover, chitosan films loaded with GFs, such as BMP-2, showed premioblastic cell adhesion, increased proliferation, and increased bone marker expression in vitro.88a−c,99b Promising results have also been reported for chitosan coated Ti surfaces in vivo.99c,d Chitosan coating alone resulted in improved osseointegration in rabbit implantation models,99c while various studies report on the bone-forming influence of Ti implants coated with chitosan films loaded with BMP-2.99b,d,e Additionally, chitosan coatings have been also tested for the delivery of antibiotics in vivo.100 On the other hand, there are many investigations that have focused on the preparation of ceramic/biopolymer101 biocomposite coatings with a view to decreasing the brittleness of the ceramic coating and enhancing cell interactions. For example, chitosan has been incorporated into CaP coatings on Ti surfaces, resulting in improved drug immobilization ability. Additionally, chitosan/CaP biocomposite coatings have been shown to be suitable drug delivery candidates, for example, the drug gentamicin was loaded in chitosan/CaP biocomposite coated Ti implants, with reported increased bioactivity and antibacterial activity.88d 4.2.2. ECM Proteins and Peptides Coatings. In recent decades, the proteinaceous components of bone tissue ECM have been applied as organic coating agents. These coatings have been shown to improve the interaction between implant surfaces and the surrounding bone tissue. ECM biomolecules such as collagen type I, fibronectin, vitronectin, and bone sialoprotein have been successfully immobilized onto bone implants, activating the implant surface and guiding cellular behavior.4b 4.2.2.1. Collagen Type I. Collagen type I is a dominant component of bone ECM and assumes approximately 90% of the osteoid phase. Its biodegradable character, low antigenicity, and cell-binding properties make it an interesting and eligible material for osteoinductive biomolecular coatings, making it one of the most studied proteins for the enhancement of implant bioactivity.86,102 In vitro, Morra et al.89a observed that collagen coatings covalently linked onto Ti surfaces were biocompatible, showing no cytotoxic effects to osteoblastic cells. Furthermore, in vivo experiments with these implants

modified through a wide spectrum of techniques, with specified, defined, and well-known compositions. In contrast, natural polymers present complex structures in vivo. Therefore, it is very challenging to reproduce their synthesis in a homogeneous form.8 Considering these factors, though the virtues of these natural based systems are obvious, their complex and unique composition constrains their possibile use clinically.74c,84b,92 4.2.1. Coatings Containing Polysaccharides. 4.2.1.1. Glycosaminoglycans (GAGs). Glycosaminoglycans (GAGs) are extracellular matrix components that have been applied as implant coating agents. Their interaction and specific recognition by implant-surrounding cells increases implant biocompatibility.8,74c,93 Chondroitin sulfate (CS), a glycosaminoglycan, has been shown to interact with other ECM molecules and osteoblastic cells.94 In in vitro experiments, the negative charge of CS, which is related to the sulfate component, facilitates the acceleration of ECM-binding to integrins and the formation of focal adhesion sites, thus improving cell attachment.8,74c Furthermore, CS has been used in combination with other molecules, such as collagen, with positive outcomes for osteoblast and osteoclast attachment in in vitro studies.4b In vivo experiments have shown that CS-collagen coatings over titanium implants expedite early bone remodeling around the implant area, which is an indicator of increased osseointegration. Additionally, chondroitin based coatings combined with collagen and RGD peptides on Ti implants resulted in increased bone density and improved bone implant contact, compared to other polymeric coatings.87 4.2.1.2. Chitosan. Chitosan is a natural cationic polysaccharide obtained from renewable resources, which has numerous and interesting biological properties. It is derived from the alkaline deacetylation of chitin, a natural component of arthropod and insect exoskeletons, crustacean shells, and fungi cell walls. Notably, it is biocompatible, biodegradable, and has antibacterial and wound-healing properties.93 These favorable traits, along with chitosan’s excellent filmogenic, hemostatic, and good adsorption properties, make chitosan a very attractive biopolymer coating agent93−95 (Figure 5). It has been reported that this biopolymer enhances bone and cartilage tissue formation due to its structural similarity to GAGs.93 However, chitosan exhibits poor solubility and mechanical properties. To reduce these drawbacks, chitosan has been chemically modified. Some of these chitosan modifications, such as the incorporation of carboxymethyl, imizadolyl, or methyl pyrrolidone, have been shown to improve osteoinductive properties and result in an increase in antibacterial activity.96,97 Other alternatives to tackle chitosan’s limitations are based on its combination with other natural polymers, such as alginate and pectin. Coatings of such combinations can 1253


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implanted in rat femoral defects. Twelve weeks postsurgery, a 2-fold increase in bone volume was observed, confirming their potential in bone healing.90c 4.2.3. Blood and Platelet-Rich-Plasma. Platelet-rich-plasma (PRP) is a small fraction of autologous blood which contains a high concentration of platelets. It is mainly composed of a fibrin matrix in which platelets are dispersed. In addition, it contains GFs and cytokines, which can directly influence cell behavior.57 Recently, PRP has been incorporated in dental implant surgery as an interesting strategy to potentially increase Ti bioactivity. PRP is obtained by centrifugation of the patient’s own blood and then directly deposited as a gel onto the Ti implant. This procedure has achieved promising results with improved bone regeneration.57,91a PRP action starts at early stages of Ti implantation, supporting a provisional 3D fibrin matrix with a complex and enriched environment over the Ti surface. The presence of PRP at this point facilitates neovascularization and osteoblastic cell recruitment, accelerating Ti osseointergation and contributing to implant success.91a,c In a model comprising osteoporotic bone from ovariectomized rats, PRP enhanced the mechanical stability of TiO2, increasing osteogenesis at the local implantation site, thereby improving the Ti osseointegration process.91b

showed an increase in bone growth and bone−implant contact area, when they were applied as healing agents for rabbit femur bone defects.89a In another in vivo study developed by Ritz et al.,103 collagen coatings onto Ti and Ti-nitride implants improved the long-term integration and stability of dental implants. Sartori et al.89b evaluated the functionalization of collagen type I on Ti surfaces. When these implants were inserted into the femoral condyle of healthy and osteopenic rats, increases in total bone to Ti contact and bone ingrowth, even in compromised bone tissue, were observed.87 Unfortunately, from an implant coating perspective, collagen presents a fast degradation rate, a low biomolecule retention capacity, and poor antimicrobial activity.102a,104 Thus, in an effort to emulate the benefits of collagen I and minimize the drawbacks, collagen-mimetic peptides have been developed as implant coating agents as an alternative option. Coatings prepared from these peptides have been shown to reduce bacterial adhesion and present osteoinductive cues.104a Alternatively, collagen has been modified to increase its mechanical strength by the addition of a mineral bone phase, while its bioactivity has been improved by the incorporation of GFs, arginine-glycine-aspartate (RGD) peptides, or polysaccharides such as glycosaminoglycans and alginate.87,89c,d,105 Interestingly, the successful incorporation of BMP-2 in collagen coatings has been shown to achieve promising results in terms of bone formation around Ti bone implants.105b,106 4.2.2.2. Arginine−Glycine−Aspartate (RGD) and Other Short Peptides. An alternative approach to activate implant surfaces is the use of short peptides sequences that are found in some large proteins, which are capable of achieving similar specific cellular interactions to the larger proteins themselves. The triamino acid arginine−glycine−aspartate (RGD) is by far the most studied of these peptide sequences, which functions to regulate cell behavior by increasing cell interactions. This adhesive peptide is localized in major extracellular matrix proteins such as collagen, fibronectin, vitronectin, and laminin, becoming the predominant binding site for cells via integrin receptors.90a,106b RGD, when immobilized in polymers such as spider silk protein, chitosan, collagen, or alginate, encourages the induction of cell adhesion around bone implants. In this way, RGD has shown beneficial effects on increasing new bone formation, thereby facilitating the mechanical fixation of Ti implants.90b,107 However, in in vivo models, it was observed that osteoblast differentiation was downregulated. Bell et al. observed that RGD/KRSR (lysine−arginine−serine−arginine peptide) immobilized in poly lysine/polyethylene glycol coatings (PLL-g-PEG) inhibited osteoblast differentiation in comparison to titanium surfaces without ECM peptides, while KSSR (lysine−serine−serine−arginine peptide) coatings resulted in decreased cell numbers and stimulated osteoblast differentiation, by increasing bone marker expression in in vivo conditions. This study confirmed the highly regulated nature of bone matrix homeostasis, where small changes in first adhesion stages can compromise cell differentiation and bone cell matrix deposition.108 Several types of amino acid sequences, ranging from the tripeptide RGD to longer derivative peptides such as GFOGER, PHSRN, or GRGDSP, have been successfully immobilized onto biomaterials and function similarly to RGD,90c,d indicating their promise for use in Ti implants. In fact, in some cases their activity has been reported as higher than that of the whole protein. For example, GFOGER, a peptide derived from collagen, was absorbed on the surface of PCL scaffolds and

5. CLINICAL STUDIES At this point, it should be noted that only a limited number of implant surface-modification techniques have made it to clinical trials and onto commercialization, while the vast majority of coatings are still in a preclinical phase.109 It is worth mentioning that the main reason for this lack of progress is the cost related to industrial upscaling and the cost-effectiveness itself. Table 3 summarizes some of the commercial Ti implants currently available and their respective surface modifications,15,109 all of them aimed at oral implantations. In this section, we summarize some of the approaches already translated to clinical settings. 5.1. Physical/Chemical Ti Surface Modifications. Dental implants modified through sandblasting and acidetching are quite common at the commercial level and have been evaluated in clinical trials. These surface techniques, frequently used in the biomedical market (see Table 3), produce high levels of surface roughness. These implants with macroroughness and microtopographic features have a survival success rate of 98.8% for up to 10 years.110 The anodization of dental implants has also been tested in clinical trials, showing increased bone-to-implant contact compared to machined Ti implants.111 Moreover, in addition to increased roughness, anodization also imparts a Ti dioxide layer to the implant which acts to prevent biofilm formation, thus enhancing their safety in terms of possible infections.15,112 5.2. Inorganic Coatings. Some of the inorganic ceramic coatings mentioned in section 3 of this review have been clinically studied,113 with some reaching commercial availability (see Table 3). Focusing on clinical trials, Chen et al.114 performed a meta-analysis from 12 randomized controlled trials and nine observational studies comparing HA coatings and porous Ti implants in hip arthroplasty. The clinical and radiographic effects of the HA coating were superior to porous Ti, as the HA coating increased the osseoconduction of the implants ensuring better implant fixation. In a similar kind of surgery, Kim et al.115 compared the clinical and radiologic results in 55 patients (110 hips) with porous-coated Ti stems that were treated and not treated with HA coatings. After 16 1254


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years, the cumulative survival rate for the stem was 100% and for the cup was 89% in both test groups, which suggests that the HA coating on the porous surfaces did not improve or diminish the results of total hip arthroplasty in the long term.114,115 Flatøy et al.116 in a 5-year randomized controlled trial compared the migration pattern and periprosthetic bone remodeling in a cementless femoral stem on HA coatings that were electrochemically deposited or conventionally plasma-sprayed. No clinically relevant differences were observed between HA coated stems in terms of stability or periprosthetic bone loss.116 A similar study was performed to evaluate the midterm effects of different Ti alloys and HA coatings used for femoral components in one-stage bilateral total hip arthroplasties. After an average of 5 postoperative years, all hips showed excellent clinical and radiological outcomes,.117 Concerning ceramic-coated dental implants, there has been some uncertainty in some clinical trials regarding the long-term stability of plasma-sprayed HA coatings and long-term clinical outcomes.118 However, more recently developed biomimetic CaP deposition techniques show a 1-year survival rate of 100%, while the mean marginal bone level change showed no significant difference when compared to that of untreated control implants.15,119 Ceramic coatings obtained using discrete crystalline deposition (DCD), a kind of biomimetic coating technique, exhibited higher CaP to implant adhesive forces than CaP coatings deposited using other techniques. Commercial Biomet 3I Nanotite is an example of a titanium dental implant that is subjected to acid-etching treatment followed by DCD to obtain a ceramic coating15 (see Table 3). In a prospective 1year clinical trial, these surfaces demonstrated good osseointegration, low bacterial attachment, and a survival rate of 99.4%.120 Similar CaP coatings, with nanotopography and HA-like structures, have also shown high survival rates (94.9%).121 Munzinger et al.122 performed a prospective study regarding the stability of a flattened pole Ti press-fit cup, and whether the addition of a HA coating leads to faster bone ingrowth into the porous coating. The flattened pole cup provided excellent early stability, and no advantage could be detected with the addition of a HA coating. In a similar randomized clinical study, Ullmark et al.123 analyzed bone formation on porous and calcium phosphate-coated acetabular cups, and observed higher bone forming activity in HA coatings. Moreover, Prudhon et al.124 performed a nonrandomized, prospective study of patients receiving a primary hip arthroplasty with a HA coated uncemented dual-mobility acetabular cup and a cemented femoral component. The implant survival 6 years after surgery was impressive at 98.4%, with low rates of dislocation.124 5.3. Drugs as Antiresorptive Coatings. Biphosphonate coatings have been tested in 20 patients with medial knee osteoarthritis receiving different treatment options, bisphosphonate-coated external fixation pins, HA-coated pins in the tibial metaphysis, and uncoated pins in the shaft. The clinical data obtained suggest that a bisphosphonate coating enables metaphyseal fixation similar to HA coatings, much better than their uncoated counterparts, though no differences between coated and uncoated pins in the cortical bone were observed.125 In a randomized clinical trial on 16 patients, dental implants with a bisphosphonate-eluting fibrinogen coating showed significantly enhanced mechanical fixation compared to

Zimmer Dental: MP-1

blasting process and acid washed/ etched grit blasting, acid treatment, and calcium phosphate impregnation grit blasting with HA particles and washing with nonetching acids

Particles with high speed are projected against implant surface. Process yield increases implant fixation and long-term stability for hard and soft tissues. After a large grit sandblasting process, which produces macroroughness, the implant surface is either washed with nonetching acids or etched with strong acids to obtain microroughness. These implants provide fast wound healing. Enhanced osteoblast growth and acceleration of bone mineralization in the newly formed bone. Increases host-to-implant biocompatibility and biomechanical response. HA has the ability to form a strong bond between the bone and the implant. Increased bone apposition for long-term success. Dentsply, Ankylos; Astra Tech, TiOblast; Zimmer Dental, MTX Sweden; and Martina, Syra Camlog, Promote; Dentsply, OsseoSpeed; Dentsply, Friadent plus; Straumann, SLA Intra-Lock: Ossean

acid-etching and discrete crystalline deposition (DCD) blasting process Biomet 3I: Nanotite

Process results in improved osseointegration and implant stability. Implant surface with protective layer, honeycomb pattern, and small pores. High roughness achieved through the injection of powdery Ti into a plasma torch under high temperatures. Increased micro- and macroroughness of Ti implants. This surface enhances the potential of osseointegration even in the early stages of peri-implant bone healing. Individual crystals of CaP deposited onto the osseotite implant surface and occupying approximately 50% of the surface. anodization laser ablation plasma spraying acid-etching Novel Biocare: TiUnite BioHorizons: Laser-Lok Straumann: ITI Biomet 3I, Osseotite; Hexagon, Cecyte

surface treatment commercial product (provider and commercial name)

Table 3. Summary of Some Examples of Commercially Dental Implants

providers claims


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that of uncoated analogues, measured by resonance frequency analysis.126

Enrique Martínez-Campos: 0000-0002-7110-3651 Alberto Gallardo: 0000-0003-4614-4299 Ander Abarrategi: 0000-0002-6510-2337

6. CONCLUDING REMARKS Titanium is the most used bone implantable material and has been applied as such for more than seven decades. Surface modifications, such as those addressed in this review, intend to improve the interactions of Ti based implants with the surrounding biological media and to overcome some of the limitations associated with Ti. Particularly, issues such as an osseointegration capability, the prevention of bacterial colonization, and the reduction of implant rejection (which may be related to the biofilm formation) are major challenges in the field. Some of the surface activation methods reported in this review have been assessed clinically, though it should be pointed out that the continuous advances in different technologies highlight the need for more homogeneous, reproducible, and customized coatings and surface treatments. The clinically most common surface treatments for Ti and its alloys typically augment roughness or porosity in order to improve some aspects of biocompatibility, like early cell attachment or biomechanical interlocking. Different kinds of coatings have been developed, using organic and inorganic materials, aiming to improve Ti implantation outcomes. An approach that has been described in many studies is based on the combination of active coatings with different active molecules such as GFs and peptides. However, this strategy does not always improve implant behavior. As an example, some studies report that bone formation induced by GFs delivered by Ti coatings could even impede the magnitude of implant-to-bone integration and disfavor final implant fixation.43,99d Despite the evident advances in the field, there are still concerns related to a definitive material with sustained release of GFs for Ti implant coating purposes.127 Besides the aforementioned bone formation and control of possible infections, which have been thoroughly assessed in the field, it is still necessary to deeply explore the effect of the immune response in implant integration and in foreign body reaction, which may result in implant failure. Therefore, a better understanding of complex host−implant interactions is needed, and Ti coating materials with defined immunomodulatory properties are still to be developed. With this in mind, strategies for triggering appropriate immune responses by functional biomaterials could be the future research focus, merging recent developments in the field of biomaterials to mimic the physiological extracellular matrix, as already discussed in this work.128 Ultimately, every application and target tissue (dental, orthopedic, etc.) requires specific optimization of the type of coating and type and load of active molecules. Thus, coatings to be developed in the future may require the incorporation of natural components present in bone, such as ECM proteins or biological factors, to bring its characteristics closer to that of the natural bone tissue.

■

Author Contributions

A.C. and E.M.-C. contributed equally to this work. A.G. and A.A. share senior authorship. Funding

The ICTP group acknowledges MAT2013-42957-R for financial support. The Francis Crick Institute receives funding from Cancer Research UK (FC001045), the UK Medical Research Council (FC001045), and the Wellcome Trust (FC001045). Notes

The authors declare the following competing financial interest(s): V.R. is employed by Noricum S.L.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Authors

*(A.G.) Tel: +34 915618806 ext. 375. E-mail: gallardo@ictp. csic.es. *(A.A.) Tel: +44 0 20 379 61183. E-mail: ander.abarrategi@ crick.ac.uk. 1256


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Titanium Coatings and Surface Modifications: Toward Clinically Useful

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