book chapter 1

328 Environ. Sci. & Engg. Vol. 10: Industrial Processing & Nanotechnology

1 Materials and Corrosion Lab (MCL), Department of Chemistry, Faculty of Science, TaifUniversity, 888 Hawiya, Saudi Arabia; 2Chemistry Department, Faculty of Science,Cairo University, Cairo, Egypt

*Corresponding author: E-mail: [email protected]

13

Future Perspectives of BiomimeticCalcium-Phosphate Coating

SAHAR A. FADLALLAH1*

ABSTRACT

This chapter consists of four main sections; each section contains 4-5paragraphs. The first one is an introduction to illustrate the aim of thischapter with three paragraphs, one of the important role and main strategyof the implant metals or as call it “biomaterials or bio metals” especiallywhen used inside the human body. The second one explain the history ofimplant modification progress that occur to improve the implant surfacesto be best compatible with the human environment. The third one discussesthe importance of improvement of the implant surfaces by coating processto enhance their biocompatibility. Although, there are great reportsconcluded the different varieties of implant surfaces as well as methodsthat play important roles to modify their surfaces, but this field still needsa high researcher's effort to submit more reports about suitable modificationmethod to improve implant surface. The fourth section in this chapteraimed to explain the future vision about the promising biomimetic Ca-Pcoating that considered the most key methods that get well the implantsurfaces.

Key words: Orthopedic and dental implants, Surface modification methods,Anodizing process, Nanomaterials, Passive and active coating,Titanium and it’s alloys, Bone tissue, Electrochemicalimpedance spectroscopy, Ca-P biomimetic coating.

329Future Perspectives of Biomimetic Calcium-Phosphate Coating

1. INTRODUCTION

1.1. Implants Orientation and Background

During the recent decade vast and continuously increasing numbers ofimplants have been introduced and attract a great attention of researchers.The term implant is used for devices that replace or act as a fraction of orthe whole biological structure. Currently, implants are being used in manydifferent parts of the body for various applications such as orthopedics,pacemakers, cardiovascular stents, defibrillators, neural prosthetics or drug-delivery system[1-3]. In general, implants are classified into dental andorthopedic.

Orthopedic implants are medical devices manufactured to replace amissing joint or bone to support a damaged bone. Joint diseases representone of the most important changing needs medical implants. Today’sestimates show that 90% of the population over the age of 40 suffers from adegenerative joint and the number of total hip replacements operation willincrease by 50% at 2030 than the number recorded at 2000 (152,000)[4,5].Cardiovascular diseases are another example where coronary stents havebecome a new standard in angioplasty procedure[6]. They are used routinelyworldwide for fixation of long fractures and non-unions, for correction andstabilization of spinal fractures and deformities, for replacement of arthriticjoints, etc. Orthopedic implant device include prostheses for hip, knee, ankle,and shoulder joints, and also include fracture fixation devices such as wires,pins, plates, screws, etc.

Dental implants are also important orthodontic products. They nowprovide a basis for prosthetic restoration, and thus the replacement ofmissing teeth by crowns, bridges, or dentures. In general, dental implantconsists of two-piece, internal fixation system abutment and externalprosthodontic restoration hold. Surgical approach and the local boneare considered most important relevant variables for excellentosseointegration[7]. In general, dental implants are used to restore lost toothby replacing both the tooth and its root.

Implanted surfaces may be metals (Ti and its alloys, Co-Cr-Mo, stainlesssteel), polymers (poly methyl methacrylate PMMA, Ultrahigh-molecular-weight polyethylene UHMWPE) and ceramics (alumina, zirconia,hydroxyapatite HA). All of them are used for orthopedic applications butonly metallic implants are used for dental application where it first insertedinto gingival so that the bone cells grow tightly around it and anchors itfirmly[8]. The main job of implanted materials is to provide mechanicalstabilization and biological aspects of bone healing to the injured bone tofacilitate the relief of pain and return the normal use of this part. In biologicalenvironment, progress necessitates a strong relationship between cliniciansand basic scientists with an engineering or biology back-ground. The main


factor that controls the choosing process of the suitable implant is to identifythe biological principle of osseointegration and to receive basic informationon implant failure. Accordingly, two important questions must be answeredbefore using the implant? The first one is the requirements for implantsmaterials? The second is the reasons that cause failure to implant materials?Four important requirements are characterized orthopedic and dentalimplants to be suitable for all parts of human body and oral environment[9],In order to serve for a long period in the determined part without failure.These requirements are summarized as the following; Mechanical propertiesare one of the properties that decide the type of materials which will beselected for a specific application as hardness, tensile strength, modulus,and elongation. The excellent match between bone and implant in mechanicalproperty is referred to as biomechanical compatibility[10]. The biomechanicalincompatibility that leads to implant failure with death of bone cells is called“stress-shielding effect”[11]thus the excellent implant that used for highservice period to avoid revision surgery must have high strength and lowmodulus[12].Biocompatibility properties show how the implant materialsreacted with the human body tissues successfully after implantationprocess[13]. The excellent implant material is expected to be highly non-toxic and should not cause any inflammatory or allergic reactions in thehuman body[14]. The bioactive implants are highly preferred as they giverise to high integration without infections[15]. On the other hand, highcorrosion and wear resistance properties are necessary for the stability ofimplants in the body environment. The release of non-desirable metal ionsby implants into the body reduces the corrosion and wears resistance. Thusdevelopment of implants with high corrosion and wear resistance is of essentialobjective for the longevity of the material in the human system[16]. Ultimately,osseointegration is the ability of implants to integrate with the adjacentbone and other tissues[17]. Appropriate implants surfaces are required forcomplete integration process. Chemistry, roughness, and topography all playa major role in the development of implant surface for goodosseointegration[18], as we will see in the following sections of this chapter.

On the other hand, the reasons why implants fail are manifold and involveaspects of surgical skills, positioning in the alveolar bone, in sufficient boneaugmentation, the loading protocol, and the patients healing capacity.Moreover, reasons of early and late failure may different; while a lack ofprimary stability is the main reason for early failure, overloading allowingan inflammation result from bacteria is the main reason for late failure[19,20].Bone graft limitations and insufficient bone augmentation can alsocontribute to implant failures[21,22]. As well as, diabetes and bad habits forpatients as smoking are not suitable for osseointegration of implants and itis one of the reasons for implant failure. Furthermore, in biological settings,metal corrodes and the degradation products likely activate the immunesystem by forming complexes with native proteins and cause, in the generalpopulation, dermal IV hypersensitivity reactions[23-25]. Currently, the


association between metal corrosion in vivo, metal allergy, and device failureis not clearly understood[25]. Whether metal allergies cause device failureor device failure results in an increase serum concentration of degradationproducts and cause metal allergies is unclear. Many patients (up to 25–60%)may have hypersensitivity metal test either the implant failed or not[23].

Due to dental and orthopedic implants have become vital fields becausethese materials can enhance the quality and longevity of human life. Thischapter will present an overview of implant surfaces especially metals withan explanation of the difference between classic, current and recentlyimplant metals and discuss the development processing that apply to improvethe surface of metal implants towards positive biological response to extendthe life of implant in the human body with good performance.

1.2. Classical Implants Biometals Used in Developing andDeveloped Countries

For the past decades, Austenitic stainless steel and cobalt – based alloyshave been used as internal fixation devices in orthopedic implants materialsfor bone plates and screws. These metals are strong, cheap, and easier tomachine[26]. Toxic elements such as Ni, Cr and Co are found and releasedfrom stainless steel and cobalt-chromium alloys due to the corrosion in thebody environment and they cause different diseases on the longtime[27].Although, these materials have low corrosion resistance, they exhibitmechanical properties combined with the low cost and low osseointegrationwhich make these materials used for temporary internal implants[26]. Metal-on-metal (MoM) hip implants made of cobalt – chromium molybdenumimplant (CoCrMo) alloy. First generation MoM hip implants were introducedin 1950s.

In developing country, among all the metallic material, stainless steelis the most popular because of their relatively low cost, ease of fabricationand reasonable. However, stainless steel is susceptible to a number oflocalized corrosion, such as pitting and crevice corrosion, Intergranularcorrosion (IGC), stress cracking corrosion (SCC)[28]. A number of failuresof stainless steel materials during its implantation have been reporteddue to their high nickel content and to the effect of aggressive ions.Stainless steel is iron-base alloys with a minimum of 10.5% Cr as an alloyingelement, needed to prevent the formation of rust[29]. Although stainlesssteel is seldom used in developed countries as permanent implants, it isstill the most used in emerging countries[30] for permanent and temporaryapplications. Typical temporary applications are plates, modular nails,screw, pins, sutures and steel threads and networks used in fixingfractures[31]. Many researchers reported the role of inhibition effects ofmany ions as OH–, NO3

3–, SO42–, ClO4– and acetate ions on pitting of

stainless steel in chloride solution[32].


1.3. Current Implant Biometals

Recently, medical market with many clinicians recognizes one of valve metal(including Ti, Al, Ta, Nb, V, Hf, W), titanium is consider as an excellentimplant materials. The mechanical and physical properties of these materialsdiffer significantly than stainless steel and cobalt chromium alloys. Thenatural selection of titanium – based materials to use as an implants is dueto the combination of its outstanding characteristics such as high strength,low density (high specific strength), high immunity to corrosion, non-reactivity with body environment (inert), enhanced biocompatibility, lowmodulus, and high ability to join with bone and other tissues. Titanium ischaracterized also by an extreme oxide layer (titaniaTiO2) whichspontaneously forms on its surface when exposed to air or other oxygencontaining environments. This oxide passive layer is typically 2–5 nm thickand is responsible for increases immunity to corrosion of titanium and itsalloys. Therefore titanium and its alloys are widely used in orthopedic anddental applications[33].

For dental implantology, zirconium and its alloys may offer a usefulalternative to titanium. Zirconia ZrO2, the oxide film on zirconium, has anopacity which makes it to resemble the natural teeth the bright white color,unlike titanium implants which give an unnatural bluish/ gray appearance.Similar to titanium, minimal ion release is detected after corrosion test orimplantation process hence, zirconia is considered to be highlybiocompatible[34]. Zirconia implants have been reported to integrate well inthe jaw bone because these materials have shown fewer inflammatoryinfiltrates in soft tissue than for titanium[35]. Many animal studies wereperformed to investigate and compare the osseointegration of 14 zirconiaand 7 titanium dental implants in mini pigs[36]. At the end of a healingperiod of 4 weeks, a histological analysis of the soft and hard tissue and ahistomorphometric analysis of the bone–implant contact (BIC) and relativeperi-implant bone-volume density (rBVD) was performed. Today, zirconiaimplants have to undergo the same development process, including surfacemodifications and adaptation of the implant geometry, as titanium implantshave undergone. For both zirconia and titanium implants surface have beenshown an intimate connection to the neighboring bone and both achieved aBIC of 53%[37, 38].

Nickel titanium alloy (NiTi) is one of the most promising titaniumimplants due to it has novel properties as shape memory effect, superplasticity and high damping properties as well as high strength (1000 MPa),low young modulus (15 GPa), large compressive ductility (>7%), largerecoverable strains (>6%) and high energy absorption (>30 MJ/m3)[39].However, NiTi alloy finds wide medical applications which include dentalorthodontic wires, intravascular stents, bone fractures fixtures, etc. Morereports from researchers are required to investigate the release of toxic Niions in soft tissue than the suitable concentration[40]. This chapter was


summarized the main aspects for orthopedic applications related with currentimplant in particular titanium and its alloys.

1.4. Future Aspects

However, the native spontaneous TiO2 film with chemical composition 14.8at% of Ti, 46.8 at% of O, C 30.9 at% with some traces of N, Si, Ca, pb, Zn,and Cu[41] detected by X-ray photoelectron spectroscopy. This passive filmis not bioactive enough to form a direct bonding, which means the lack ofosseointegration to implant- bone interface and might lead to long termfailure after implantation[42]. Specifically, the 10 to 15 year lifetime of currenttitanium-based orthopedic implants is not as expected by many patients[43].Itis important to understand the interaction between the host bones and thetitanium implant in a living body, which occur mostly in the bone – interface.All research reports indicated that surface characterization of implantscontrolled such interactions[44]. Many attempts have been made to improvethe surface properties of titanium-based implants include surfacemorphology, surface chemistry, and surface energy, which significantly affectthe initial bone cell’s responses to the bone – implant interface[45]. Thesurface energy of implant is determined by the material’s surface chargedensity and net polarity of the charge. A surface with net positive or negativecharge may more hydrophilic and it became suitable as implant. Due to thepresence of negative charge TiO2 layer on titanium implant, it consideredas guest appropriate in host tissues[46]. After surface modification methods,a better bonding ability with bone has been achieved due to the creation ofoptimum micro/nano scale surface roughness, a more favorable surfacechemistry, and/or a new morphology preferred by bone-forming cells (orosteoblasts).The following sections will discuss in detailed how to improvethe implant titanium surface by applying a variety of surface modificationsmethods and which one is suitable for implant titanium surface.

2. ADMINISTRATION STRATEGIES FOR IMPLANT SURFACEMODIFICATION

Until now, two approaches are accredited and used for the preparation ofnanomaterials, which includes the top-down strategy and the bottom-upstrategy. In top-down strategy, nanomaterials can be formed by breakingup bulk materials into much smaller sizes ranging from micro to nanometerscale, according to this strategy the nanomaterials fabrication takes placefrom the top bulk state (macro scale) to the nano scale (down to nanometer).In a like manner, in the bottom-up strategy, the nanomaterials can beprepared atom by atom in the range of nanometer. The shape and size ofthe nanomaterial can be effectively controlled using the bottom-up strategy,which is not achieved by top-down strategy[47]. Bottom- up strategy is simplyknown as self-assembly, where the atoms or molecules occur within the


nanometer scale from the bottom range 0.1nm up to 100 nm, see Fig. 1,which it consider the most important strategy to improve the titaniumimplant surface[48].

In this regard, a current strategy is to modify titanium-based implantsto possess nanometre surface features considering that natural bone is ananostructure material. So modification methods of implanted surfaces playan important role to change morphology or chemistry of titanium surfaceto obtain surface that mimics the bone or designing a new implant similarto that of bone is a challenging problem in the field of implants materials.Furthermore, reduced Infections encourage cell adhesion can be obtainedby appropriately tailoring the surface chemistry of implant to possesantibacterial properties that enhance the osseointegration process afterimplantation surgery.

Physical methods, laser beam processing, mechanical techniques(grinding and polishing). Wet chemical methods, Organic synthesis, Self-assembly, Colloidal aggregation.

As illustrated, the development of the surface is not only highly influencedby the surface chemistry, but also more specifically by nano/micro metretopography[49]. Nanophase materials are future generation orthopedic anddental implants that currently used due to their sufficient bonding withbone. Nanophase materials possess unique surface properties which aresimilar to the bone and have rough surface[50]. An optimal bone response isoccurred with a moderately rough surface being as a surface area roughness(Sa) level of between 1 and 2 µm[51,52]. This can be attributed to the increasedprimary stability as roughness supports the friction of the implant withbone. This roughness can exceed a critical level where the friction decreasesagain. On the other hand, other additional explanation that focuses oncellular aspects, the interaction of the surface, and the adsorbed moleculesand the cells. Otherwise, nanograined materials are characterized by lessnumber of atoms in each grain and very high atoms on the surface andhence posses large surface energy. The variation in the surface energydue to the nano surface roughness leads to high density of osteoblastsadhesion[53-55]. Surface modifications can provide graded functionality, aswill be discussed later, and are generally divided into two categories: surfaceconcave texturing, which achieved by chemical and electrochemical methods,and surface convex texturing, which achieved by physical or chemical

Fig. 1: Strategies for manufacturing nanomaterials.


depositing method. In the following sections, a variety of surface modificationmethods will be discussed to illustrate the recently methods used to optimizethe surface implant interface.

2.1. Physical Administration

Physical methods play an extremely role to modify the surface of titaniumand its alloys such as thermal spray, physical vapor deposition, Ionimplantation and deposition and glow discharge plasma. Thermal sprayingis a process in which materials are thermally melted into liquid dropletsand introduced energetically to the surface on which the individual particlesstick and condense. It divided into flame spraying and plasma spraying[56].The principal difference between flame and plasma spraying is the maximumtemperature achievable. The coating is formed by a continuous build-up ofsuccessive layer of liquid droplets, softened material domains and hardparticles. In addition to these two techniques, other thermal sprayingtechniques such as arc spraying, detonation gun spraying, laser spraying,and high velocity oxy-fuel (HVOF) spraying, are widely used in theindustry[57]. One of the most important surface physical modificationmethods is physical vapor deposition PVD. The target materials by thisprocess are evaporated in vacuum or sputtered to form atoms, moleculesor ions that are subsequently transported to the substrate surface, on whichcondensation and sometimes some reactions with the materials surfacetake place leading to film growth. PVD processes are characterized by highcoating density and strong adhesion, multi component layers, low substratetemperature, and myriad of coating and substrate materials. PVD processesinclude evaporation[58], sputtering[59], and ion plating[60].

Ion implantation and deposition process is also an important physicalsurface modification in which energetic ions are introduced into the surfacelayer of a solid substrate via bombardment. By this method there is apossibility of introducing a wide range of atomic species independent ofthermodynamic factors thus making it possible to obtain impurityconcentration and distributions of particular interest. This method includestwo types: conventional beam – line ion implantation and plasma immersionion implantation (PIII). On the whole, ion beam technology has contributedsignificantly to modify biomaterials[61] through formation of surface modifiedlayer or that of a thin film that can be totally different from the substrate.Furthermore, implant ions help to promote the formation or enhance theeffectiveness of existing protective passive film[62-67].

2.2. Chemical and Electrochemical Administration

These methods included chemical treatment, electrochemical treatment(anodic oxidation), sol-gel, chemical vapor deposition (CVD), and biochemical


modification. For all the pervious methods, except CVD, chemical,electrochemical or biochemical reactions occur, respectively, at the interfacebetween implant surface and a solution. While, CVD is a process involvingchemical reactions between chemicals in the gas phase and the samplesurface resulting in the deposition of a non-volatile compound on thesubstrate. In the sol-gel process, chemical reactions do not occur at theinterface between the sample surface and solution or gel, but rather in thesolution. Chemical treatments include acid[68], alkali[69], H2O2

[70], heat[71],and passivation treatment[72,73].

Anodization of implants surface is considered as a powerful chemicaltool to control the nanoscale (1D-3D) of titanium oxide (titania) and zirconiumoxide (zirconia) coating films. Anodic oxidation encompasses electrodereactions in combination with electric field driven metal and oxygen iondiffusion leading to the formation of an oxide film on the anode surface. It iswell – established method, Fig. 2. To produce oxide films on metals. Thismethod is benefit for biomaterials to increase the oxide thickness to increasecorrosion protection and decrease ion release, coloration and porous coatings.Typical anodization procedures include alkaline cleaning, acid activation toremove the native TiO2 and surface contaminants, and electrolyte anodizing,which usually has a three- electrode configuration (titanium anode, platinumcathode and Ag/AgCl reference electrode). The structural and chemicalproperties of the anodic oxides can be varied over quite a wide range byaltering the process parameters, such as anode potential, electrolytecomposition, temperature and current.

The main chemical reactions for anodizing titanium are listed below(from equation 1 to 5 adapted from[74]

At the Ti / TiO2 oxide interface: Ti Ti 2+ + 2e– (1)

At the Ti oxide / electrolyte interface:

Fig. 2: Schematic diagram for anodizing apparatus.


2H2O 2O2–+ 4H+ (2)(oxygen ions react with Ti to form oxide)

2H2O O2 (gas) + 4H+ + 4e– (3)(O2 gas evolves or stick at electrode

Surface)

At both interfaces: Ti2+ + 2O2– TiO2 (ATO) + 2e– (4)

The final oxide thickness, d, is almost linearly dependent on the appliedvoltage

U: d a U (5)

Where a is usually a constant within the range 1.5-3 nm/V4.

To date, It is well known that among all the synthetic procedures anodicoxidation of Ti is an excellent approach to fabricate TiO2 nanopore/nanotubearrays with long-range order structure due to its simplicity and low cost.According to Fig. 2, many electrolytic solutions are widely used for theanodization of Ti to prepare titania such as: phosphoric acid-H3PO4, sulfuricacid-H2SO4, acetic acid-CH3COOH, and others, neutral salts and alkalinesolutions[75, 76].The most important advantage of anodization process routelie in its ability to tune the surface morphology of Ti and its alloys for betterbiocompatibility and bioactivity by controlling and adjustable the anodizationexperimental condition[77-79]. Furthermore, the nature of electrolyte is playa key role in determining the type of morphology formed. The anodic TiO2film will develop a porous/tubular morphology by the presence of fluorideor perchlorate, chloride or bromide ions, while in other electrolyte theTiO2 film will be of barrier films[80-84], see Table 1.

Table 1: The different morphologies of titanium oxide obtained by anodization (adaptedfrom Ref. 84)

Barrier type Nanoporous and nanotubular type

Structure Thin (few hundreds of nm) • Inner layer at M/MO interface:and compact thin (< 50 nm), barrier type.

• Outer layer at the MO/electrolyteinterface: porous/tubular form (upto Ãº 1000 µm)

Electrolyte Solutions of sulphuric, • Aqueous and organic solutionphosphoric, acetic acid. containing fluoride ions.

• Aqueous and organic solutioncontaining perchlorate, chloride,bromide ions.

Anodic spark oxidation is also called micro-arc oxidation (MAO) or plasmaelectrolytic oxidation has been suggested to prepare a porous, adherent,and rough titania coating which enhances bioactivity, hydrophilicity, cellular


reaction and corrosion resistance of the implants in body[85-88]. This techniqueis benefit to deposit apatite coating on Ti surface due to high applied voltageduring MAO process can accelerate electromigration process of the ions inelectrolyte, which attracts more Ca2+ and PO4

3- ions to incorporate to titanialayer by redox reactions in the electric field and promote the formation ofapatite[89,90]. The quality of MAO coating is determined also by the sameanodization parameters[90].

Chemical vapor deposition (CVD) is a process involving chemicalsreactions between chemicals in gas phase and the sample surface resultingin the deposition of a non-volatile compound on the substrate. It is differentfrom PVD which typically employs techniques, such as evaporation andsputtering involving no chemical reactions[91].

2.3. Future Aspects

Fracture healing and success regeneration process is a complex biologicalprocess due to it depended on many potential factors including patientcharacteristics (e.g., chronic systemic metabolic disease, metabolic disease,chemotherapy, smoking, excessive alcohol use, diabetes, medications, poorcompliance with rehabilitation), local factor (e.g., difficult anatomical site,high degree of fractures, extensive injury to the soft tissue bed, infection,poor vascular supply, irradiation), and surgical and implant factors(suboptimal bone reduction, surgical technique, or application of the implant,inadequate implant characteristics)[92]. These facts have stimulate futureresearch into how improve the implant surface characteristics to becompatible with biological milieu in order to help ensure a strong bonehealing response. These implants of the future will hopefully modulate thelocal environment in a suitable manner with minimal risks, to improvesurgery implantation outcome and enhance patient life.

3. PROGRESS IN SYNTHESIS OF BIOMIMETIC COATING

Natural bone is nano and macro architecture nature; see Fig. 3, so there isa physiological relation for the use of porous implant for the replacement atdefect sites. From just mimicking the natural organization of bone a porousstructure also helps in the supply of blood and oxygen to the implant interfaceand facilities bone in growth at the interface. The modification of implantaimed to be porous is achieved by physico-chemical modification as seen inthe previous sections. All these modification methods can be altered bysurface energy; surface charge and surface composition to enhance materialsand biological response, all studies confirmed that surface coating techniqueis considered as the most important method used to achieve this target.

Nanoporous substrates and coatings distinguished by their large surfacearea have recently attracted attention in orthopedic implants due to they


enhance fractures roughness and, plasticity, and biocompatibility,hemocompatibility, and mechanical compatibility[93]. One of the mostcommon complications associated with dental and orthopedic implants isbacterial infection. Bacterial colonization and biofilm formation on implantsmaterials may lead to acute and chronic inflammation of the underlyingbone and the adjacent soft tissues[94]. The biofilm formation ofmicroorganisms can lead to in growth bone, nonunion of the fractures, andimplant loosening because it is involved in clinical infection and resistanceto antibacterial agents[95]. There have been many studies regardincorporating antibacterial agent into the coating of biomedical implantsfor improving the antibacterial properties[96]. Coating implants withantibacterial agents can be classified into two classes as passive and active,depending on the type of antibacterial agent’s delivery.

3.1. Passive and Active Coating

Passive coating does not release bactericidal agents to the host tissues andrather kills bacteria upon contact. The surface characteristics of implants,such as its roughness and chemistry, hydrophilicity, surface energy, surfacepotential and conductivity, play an important role to form passive coatingswhich can prevent bacterial adhesion. Modification of the physicochemicalsurface properties of the implant is a simple and economic way to cancelbacterial colonization, For example, ultraviolet light (UV) irradiation, whichcan inhibit the bacterial adhesion by increasing the wet ability of TiO2layer[97,98]. Other studies have shown that the modified crystalline anataseTiO2 significantly reduces bacterial attachment[99]. On the other hand, coated

Fig. 3: Structure of bone tissue [S. Sprio et al./Journal of Biotechnology 156(2011)347–355].


titanium surface by using hydrophilic polymer such as polymethacrylic acid,polyethylene oxide or protein resistant polyethylene glycol can be appliedto significantly inhibit the bacterial adhesion[100]. Recent studies concludedthat biosurfactants can be applied as anti-adhesive or antimicrobialcoatings[101,102].

Active coatings can release the bactericidal agents to the host tissuesto prevent potential infection. Coatings with antibiotics are considered asthe best example of the active coatings, where the ideal antibiotic deliverycoating should release antibiotics at optimal bactericidal level for asufficient period of time to do two important things; to prevent infectionand to stop the risk of developing antibiotic resistance[103]. Clinical studiesreported that loaded antibiotics bone implant can decrease deepinfection rate after the implantation process in host tissue sites[104]. Thereis a recorded of large number of antibiotics coatings for the orthopedicimplants with broad antibacterial spectra, e.g., Gentamicin[105], cephalothin,carbenicillin, amoxicillin, cefamandole, tobramycin, andvancomycin[106,107].

Recent studies pointed to the antibiotic hydroxyapatite (HA) coatingswhich exhibit significant improvement by preventing infection comparedwith standard HA coatings, but many studies are required regarding themethodology of antibiotic incorporation into the HA coating and theadjustment release kinetics.

3.2. Creation of New Type of Biomimetic Coating

The pervious sections are confirmed that titanium oxides with differentnanostructures, which depended on the method of preparation, are formedon titanium surface. Titanium oxide features has excellent biocompatibility,and since it is a hard material, resist damage. In order to increase thethickness and bioactivity of titanium oxides, methods of applying calciumphosphate – based materials are being actively investigated with the aim ofenhancing osteoinduction of titanium surface. It is well known that, calciumand phosphate ions are present in physiological media and can be adsorbedon titanium oxide film surface with various percentages. The adsorption ofcalcium phosphate on TiO2 films was found to increase by increasing theimmersion in the simulated physiological solutions[108-111].

Hydroxyapatite (Ca10(PO4)6(OH)2) and materials of major interest for loadbearing implant applications, Brushite (CaHPO4.2H2O), Octacalciumphosphate (Ca8H2[PO4].5H2O) and calcium hydroxyapatite are prominentcalcium phosphate salts found in bone[106], but crystallographicallyhydroxyapatite (HA) is the dominant lattice structure of hard tissue.Therefore, there has been a tremendous interest in using syntheticallyderived HA for regenerating bone at the defect sites. HA can be synthesized


from biological skeletal carbonate by hydrothermal exchange as per thefollowing reaction:

10CaCO3 + 6(NH4)2 + 2H2O Ca10(PO4)(OH)2 + 6(NH4)2CO3 + 4H2CO3

It also gets mineralized in situ on implants made of tri-calcium phosphateand tetracalcium phosphate, due to interactions with the serum accordingto the following equations:

H2O + 4Ca3(PO4)2 Ca10(PO4)6(OH)2 + 2Ca2+ + 2HPO4

3H2O + 3Ca4P2O4 Ca10(PO4)6(OH)2 + 2Ca2+ + 4OH-

There are different calcium phosphates salts, with 1 < Ca/PW> 2 arenot encapsulated by a fibrous tissue and allow for bone in growth to theimplant[112].

Another approach to enhancing osteoinduction is to promote theformation of hydroxyapatite on titanium in the human body. Apatite–likeCa-P-O compound can be accommodated on porous titania by immersionthe TiO2/Ti surface in saline phosphate buffer solution containing2.5mMCa2+[108]. Apatite-like compound has been examined by SEM/EDXanalysis and the improvement of stability of implant was confirmed.

3.3. Future Aspects

As a surface modification method, anodization can lead to desired chemistryand/or topography change and could be used with other treatments, ashydrothermal, together. First, anodization provides a controlled way tocreate nano-roughness or even nano-features. It is reported that increasedmicro/submicron roughness could enhance bone cell function as ALPactivity[113] and cell adhesion[114]. The future titanium implant should possessroughness in all three scales: macro, micro, and nano that will be considerideal nanophase materials for orthopedic and dental applications. Micro/nano HA films produced using anodized shows some advantages overconventional ones. Also, anodization has a strong role to incorporate Caand P into Ti coatings. The recent research still needs more investigationabout the bonding strength between apatite crystals and the anodic oxide.Furthermore, anodization can be used to incorporate drug delivery [115] intoporous titania to enhance new bone formation or as reservoirs of chemicalmediators due to titania can absorb protein and drugs that can be used forthe treatment of bone diseases such as: Paget’s disease, osteoporosis, bonemetastases, malignancy-associated hypercalcemia and pediatric bonediseases[116].

Particularly the futures studies focused on control the anodization growthfactor to obtain unique porosity titanium based implants shows significantpromise for enhancing their longevity in human body.


3. PROMISING CA-P BIOMIMETIC COATING

From a chemico-physical perspective, the mineral part of bone is a nearlyamorphous nano-structured calcium phosphate exhibiting hydroxyapatite-like crystal structure and containing ions such as CO3

2-, Mg2+, SiO44-, HPO42-, Na+, K+, Sr 2+ [117]. The bioactivity of these elements plays a relevant role

in the adhesion of cells on the implant and the subsequent activity of boneformation and remodeling. Due to the reactions between bone cells andimplants occur at the tissue–implant surface interface, so surface propertiesof implant play a major role for determined the biological response of tissueto implant and the material response to the physiological solution. Recently,most of surface modification techniques are aimed at mimicking the naturalorganization of bone tissues and there by create a suitable environment forgood bone healing. This objective attract a great attention from researchersto develop Ca-P-based surface coatings on metallic and non-metallic(ceramics) substrate for load bearing implant applications such as hip andknee joints prosthesis and dental implants[108-111]. The choice of metallicand non-metallic depends on the location and size of the bone defect andthe patient’s personal characterization.

As mentioned in the previous sections, the stoichiometric compositionof Ca-P coating is [Ca10 (PO4)6(OH) 2], hydroxyapatite (HA), which is insolubleat physiological conditions and thus has low bio-activity. Researchers forceup the research toward the incorporation of ions in HA structure to increaseits bioactivity. Osteogenic activity increases in the presence of magnesium-substituted HA due to the replacement of calcium by magnesium in surfacecrystal sites increases the number of molecular layers of coordinatedwater[118] which support protein adsorption and cells adhesion to theimplant[119]. Because of silicon is an essential trace element for metabolicprocess associated, its aqueous form has been shown to enhance osteoblastsproliferation, differentiation and collagen production. It plays a key role inthe formation of crosslink between collagen and proteoglycans which stabilizethe bone matrix molecules and preventing their enzymatic degradation[120].As well as, induced strontium ions into HA structure leads to a gain in bonemass and improve mechanical properties which enhance onto genesis[121].In general, multi-substituted HA has been also obtained in biomimeticconditions, by carrying out the nucleation of the apatite phase in simulatedbody fluid. This process mimics the physiological conditions of bone formationand allows HA incorporating ions that present in physiological solutionwhich they present in physiological environment[122].

3.1. Preparation and Characterization of Ca-P Biomimetic Coat

There are different coatings methodologies like ion beam assisted deposition,plasma spray deposition, pulsed laser physical vapor deposition, magnetronsputtering, sol-gel derived coating, electro deposition, micro-arc oxidation,


and laser deposition extensively studied at laboratory scale[122]. Severalresearchers have explored the possibility of Ca-P coating on metallic materialby chemical and electrochemical preparation based on metallic material.MAO is the most important method used for this purpose[123].During theMAO process, the component is immersed in an aqueous electrolyte bathand connected to a high–voltage power supply. Water cooled stainless steelvessel serves as the container as well as the counter electrode. This arcthermo chemical interaction induced by the high temperature (103 to104k)[124] and high pressure 102 to 103 MPa

[125] discharge channel can producehigh performance, firmly adhered oxide ceramic films on the metals. Thusmicro-arc oxidation coating technology is often used for Al, Ti, Zr, Mg andtheir alloys[126]. MAO is considered as simple, economical, andenvironmentally friendly coating technique for producing porous, rough,and firmly porous adherent coat on the surface of a metallic material.Caand P ions can be incorporated intoTiO2 on Ti substrate from Ca-P containingelectrolyte bath. On the other hand, this porous nature of HA coating canencourage the new generation bone tissue an implant and open up thepossibility for the incorporation and release of antibiotics around theimplants. Researchers found that the presence of anatase (TiO2) at 250 Vand both anatase and rutile (TiO2) at 350V. Up to 350V, No Ca and Pcontaining phases were detected by X-ray photo spectroscopy (XPS). Withfurther increase in applied voltage (500V) the Ti peak was significantlyreduced and new Ca, P, Ti and O containing compounds were formed inaddition to rutile and antase. Three dominant phases at 500V include-Ca2P2O7, CaTiO3, -Ca3 (PO4) and Ca2Ti5O12

[127]. At lower voltages theoxide layer exhibited a well- separated and homogeneously distributed porousmicrostructure[127]. The pore size increased with increasing applied voltageand at higher voltages (450V) the oxide layers cracked and the surface becameslightly rough and irregular. Time play a vital role to suggest the phase ofMAO coating, where author’s found that while CaTiO3 and -TCP and HAare formed at 1.5 min CaCO3 phases appeared only after a treatment timeof 3 min. From 1.5 to 20 min, rutile and CaTiO3 phases were reduced, -TCP phases have little change, and HA and CaCO3 phases graduallyincreased. Furthermore, the electrolyte used for MAO process was a mixtureof nano-HA, Ca-P-electrolyte solution[128]. The HA concentration in theelectrolyte was varied as 0, 4, 8, 12 and 16 g/l. The results indicated anincrease in HA concentration. The HA also effect on the Ca and Pconcentrations decreased with increasing HA concentrations and Ca/P ratiosof the coatings and about1.

Recently, different metal pre-treatments such as alkali treatments[129],acid treatments[130], H2O2 treatments[131], and anodic oxidation treatmentsin acid solution containing H2O2 or fluoride[108, 132] have been used by variousresearch groups in an attempt to form such a bioactive surface on Ti samples,where Ca and P ions can incorporate to these bioactive surfaces fromelectrolyte physiological solution. The scanning electron microscope (SEM)


with X-ray energy dispersive analysis have shown that the formation ofthick – crystallized Ca-P coating deposited on nano titania formed in H2SO4/H3PO4 mixture[132]. Phosphorous embedded in titanium oxide layer afteranodization with H3PO4 electrolyte[133]. Both Ca and P were contained inthe oxide layer with Ca/P ratio close to HA (1.67) after anodization in calciumglycerol phosphate and calcium acetate electrolytes[134]. As well as, HAcrystals were randomly precipitated on the anodic oxide film after additionalhydrothermal treatment[135]. Scanning electron microscope, SEM, showedthat HA crystals were usually columnar or need-like structure.

Anodized titanium (in H2SO4 electrolyte) with anatase and rutile titaniasurfaces were shown to form apatite layers after soaking it in simulatedbody fluid (SBF). The in vitro study confirmed that the composition andsurface morphology of the resulting apatite layers is very similar to thenatural bone[136]. Formation of good adherent layers from nano-scale HAare formed after treated anodized titanium with NaOH to form nano-fibersfrom sodium titanate followed by immersion in SBF[137].

3.2. Efficiency and Evolution of Ca-P Coating

Cell adhesion is a dynamic process involving the initial cell-protein contactfollowed by subsequent cellular response in terms of adhesion, migration,proliferation and differentiation, Fig. 4. Surface topography can influenceon all the pervious steps, so the response of implant surface toward proteinis the first indicator to the efficiency of surface. The adsorption of proteinsplays a vital role to promote the ostogenesis process at the tissue-implantinterface[138], and it depended on the type of protein and nature of the surface.The properties of protein as size (larger molecules have more sites on thesurface than smaller), charge (molecules near isoelectric adsorb readily),topography structure stability (molecules with less cross linking bondingare considered as less stable molecules), unfolding rate (molecules rapidlyunfold can form contact points with the surfaces). For great efficiency,chemical composition, heterogeneity and potential of the implanted surfaceplay the great roles to facilitate the interaction of the surface with protein.Adsorption of protein molecules may be transfer to the surface by one ormore of the following four transport mechanisms (1) diffusion (2) thermalconvention (3) flow and (4) coupled transport, such as combination ofconvention and diffusion. Hence, adsorption of proteins to the surface of abiomaterial is very important in the field of material science where it reflectthe cell adhesion responses and it detect the rate of bone remodeling processthrough changes in surface properties while still maintaining the bulkproperties of the implant, Fig. 4.

Although several experimental concerning the in vivo studies of Ca-Pbased coating have indicated a stronger and faster fixation and more bonein growth at the interface, the clinical performance are still far from beingconcluded. Hence, most of in vivo studies are only limited to animal model


experiments which can highlighted by the following points: the influence ofsurface roughness of Ca-P coated Ti implants on bone bonding and boneformation was studied by interesting them in trabecular bone of rabbits.After 4 weeks implantation period of calcium phosphate coated bead implantsnew bone was found not only on the implant surface but inside the Ti beads,whereas, after a 12-week healing period the Ti surface was almost completelycovered by new bone.

In general, the main concept for good healing process is related withgeometry and chemical compatibility at the surface which they can alleviatethe bone regeneration and bone bonding to the implant. Another fact isalso suggested for rapid bone in growth is attributed to the amorphousnature of Ca-P coatings[139].

In vitro antibacterial activity study by using the plate counting methodagainst Staphylococcus aureus (ATCC6538) indicated a significantly reducednumber of bacteria on Ca-P based on anodized Ti surface[132]. This studyconcluded that, biomimetic coating requires pretreatments of Ti surfacebecause untreated Ti surfaces cannot induce Ca-P nucleation in simulatedphysiological environments. Furthermore, nano-TiO2 surface formed fromfluoride bath exhibited antibacterial activity effectively against S-aureusoral bacterial. These results support the application of biomimetic Ca-Pcoat for dental application confirm the positive effect. Lack of coordinationamong material science and biologists is the reason for there are onlyalimented amount of in vivo studies available in the open literature and insufficient understanding of this interdisciplinary subject.

Fig. 4: Schematic illustration of the sequential reactions that take place after theimplantation of biomaterial into a living system (Adapted in Ref[122])


Electrochemical impedance spectroscopy, EIS, is a powerful, non-destructive and informative technique which is used to study the corrosionphenomena at the implant surface-solution interface and the degree ofcoating stability in simulated physiological solution[132]. By analyzing thespectra of EIS results after immersion the Ca-P anodized sample in saturatedcalcium phosphate solution, SCPS, the data confirmed that a strongadhesion present between the Ca-P-HA-like coat and the anodized titaniumsurface. As well as, the EIS fitting data, by using equivalent circuit shownin Fig. 5a, are confirmed the duplex nature of the Ca-P/TiO2 film comprisingthe inner compact layer and outer porous layer, where this study recordedthe high resistance values of Rb (barrier inner layer) and Rp (porous outerlayer) support the suggestion of high corrosion resistance and high stabilityof biomimetic Ca-P coat in bioenvironment. Also the high solution resistancevalue (Rs) is indicated the incorporation of ions from simulated solutionthrough the pores of the outer film which pointed to the porous structure ofCa-P biomimetic coat. The change of the outer porous film capacitance, Cp,can be used as indicator of the change in its layer thickness due to itsinteraction with the environment solution. The reciprocal capacitance ofthe porous layer 1/Cp is directly proportional to the thickness of passivelayer[140].

On the other hand, the experimental EIS results of anodized titanium,in H2O2/H2SO4 electrolyte, after immersion for 7 days at 37ºC in SCPScontaining different concentration of Ca2+ ions were fitted to anotherequivalent circuit model, Fig. 5b. An additional R-C combination wasintroduced to account for the relatively thick adsorption[108]. It is importantto mention that the adsorption layer thickness increases with the increaseof the concentration of Ca2+.

3.3. Future Aspects

Hope for new implant surface consist in the close reproduction of thechemical, morphological and biomechanical features of the native organ/tissue is considered a big challenge in the future. Furthermore, although

Fig. 5: Equivalent circuits used for fitting experimental impedance data (Adapted inRef[108])


the development of Ca-P coatings for improved bio-implants have beenrecognized and attract a great attention of researcher, but at this point, it’sdifficult to bring a detailed discussion on commercialization of Ca-P coatings.

Natural bone is basically a hierarchical organization at different lengthscales ranging from nanoscale to mesoscale Fig. 2. 69 wt% from humanbone is calcium phosphate and the other percent are proteins,polysaccharides, and lipids. All the studies confirmed that, at macroscopiclevel each bone cells (such as osteocytes) is made up of a strong calcifiedouter compact layer[141]. Therefore, artificial implanted materials mimickingthis hierarchical organization of the naturally occurring bone in terms ofits surface chemistry and surface topography may be the design for thefuture.

Hence surface modification of implant material is aimed to improve thebiological response through changes in surface properties while stillmaintaining the bulk mechanical properties of the implant. Therefore, therehas been a great push towards the development of Ca-P- based surfacecoating on various metallic and non-metallic substrates for load bearingimplant applications such as hip joint prosthesis, knee joint prosthesis anddental implant.

Multi-substituted HA is considered a promising approach toward thenucleation of the apatite phase in simulated body fluid (SBF) containedbiomimetic ions at 37ºC. This procedure mimics the physiological conditionsof bone formation and allows HA incorporating various ions (Na+, K+,HPO4

2–, Mg2+, SiO44+, Sr2+, CO3

2–) which they present in physiologicalsolution to enhance the bioactivity of osteogenic[142]. The initial results fromthis approach detected that, co- substitution with carbonate gave improvedof osteoblasts activity[143]. The same effect was also confirmed by the silicon-substituted HA through in vivo study[143], where the migration of Ca, P, andSi ions to the bone interface accelerated the precipitation of biologicalapatite[144]. Recent studies have also focused on the possibility to incorporateFe ions in the apatite lattice, where Fe ions play an important role tosupport implants for enzyme immobilization. Cell surface interaction andcell adhesion are complex processes occur successfully on Fe-HA whichreflect its good biocompatibility[145] and has super paramagnetic properties.In fact, the new trend for the development of the implant surface isconsidered to be more suitable for the biological environment, but also tobe a therapist for many of the health problems. Additionally, studies ofgene expression profiles from new modified implant surfaces by multi-substituted HA or others is considered a new trend gives a realistic pictureabout osteoblasts differentiation and bone formation around implants inhuman body[146]. In the present chapter, attempts are made to give anoverview of the basic principles and future perspective behind the biomimeticimplant coating as well as advantages features such as bioactivity andbiocompatibility associated with these coating.


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