Developing Nanostructured Metals for Manufacturing of Medical Implants withImproved Design and Biofunctionality

Ruslan Z. Valiev1,2,+, Evgeny V. Parfenov1 and Lyudmila V. Parfenova3

1Ufa State Aviation Technical University, 12 K. Marx street, Ufa, 450008 Russia2Saint Petersburg State University, Universitetskiy prospekt 28, Peterhof, St. Petersburg, 198504, Russia3Institute of Petrochemistry and Catalysis of Russian Academy of Sciences, 141, Prospekt Oktyabrya, Ufa 450075, Russia

Recent years have witnessed a series of numerous investigative activities to improve existing metallic biomaterials (Ti and Ti alloys,stainless steels, Mg and Fe alloys) by their nanostructuring for advanced medical applications using severe plastic deformation (SPD) processing.Nanostructured metals are peculiar for their enhanced strength and fatigue life, which makes them an excellent choice for fabrication of implantswith improved design for dentistry and orthopedics. Moreover, surface modification of nanometals by chemical etching and bioactive coatingsshow a significant improvement of biomedical properties. Various studies conducted in this field make it possible to fabricate miniaturized dentalimplants and nanoTi plates with enhanced osseointegration. [doi:10.2320/matertrans.MF201943]

(Received March 13, 2019; Accepted April 24, 2019; Published June 25, 2019)

Keywords: nanostructured metals, enhanced strength, medical implants with improved design, surface modifications, bioactive coatings

1. Introduction

Presently, over 70% of implant devices are constructedfrom metallic materials because of their strength, toughnessand durability.1) On the other hand, another principal concernin the use of metals in the human body is their safety in termsof toxicity with metal ion release, which in turn justifies theapplication of corrosion-resistance materials, mostly such asstainless steel, Co­Cr­Mo alloy, CP Ti and Ti alloys, andmore recently - bioresorbable Mg and Fe alloys. However, tohave good biofunctionality, metals should be improved withadditional properties (electrical properties, wear resistance,bioactivity and so on) before they can be used for medicaldevices.1,2)

New alloys with optimized chemical composition,manufacturing processes and surface modifications undergocontinuous research and development to satisfy the clinicaldemands for medical devices.2,3) At the same time, during thelast two decades, the nanostructuring of metals to improvetheir properties using the so-called «severe plastic deforma-tion» (SPD) processing has become a new and promisingarea of modern materials science and engineering.4,5)

Nanostructuring of metallic materials by various SPDtechniques comprises grain refinement of the microstructuredown to submicron or nanosized range as well as theformation of nanoclusters and nanoprecipitates of secondaryphase, which essentially influences the mechanical andfunctional properties of the materials.5,6) Up to now a wholevariety of SPD techniques have been introduced anddeveloped to provide heavy strains (¾ > 5­7) under highapplied pressure including multiple forging, accumulativeroll bonding (ARB), twist extrusion and other (see, e.g., therecent monographs and reviews.7­9) However, the mostpopular techniques even today are high pressure torsion(HPT) and equal channel angular pressing used for themanufacture of ultrafine-grained materials and put forwardalready in pioneer works.4) Recently, the techniques havebeen further developed for practical use.10,11)

From the perspective of medical applications, the use ofSPD processing techniques for the formation of nanostruc-tures in metals and alloys may positively affect bothmechanical and biomedical properties.12) For the latter,surface modification of bulk nanomaterials also plays animportant role.13,14) All of this provides the possibility forthe development of medical devices with improved designand functionality. This article describes the progress in recentstudies of such relevant issues.

2. SPD Processing of Nanometals for Medical Devices

2.1 Commercially pure TiThe first works in this regard were applied to commercially

pure titanium (CP Ti) because of its highest biocompatibilitywith living tissues among various metals,15) and this was thefocus of many clinical studies of medical tool and devicesapplied in trauma, orthopedic and dental practice. But unlikeother metallic materials used in biomedical devices, CP Tihas somewhat low strength properties. Typically, with higherstrength levels resulted from either alloying or secondaryprocessing, the materials usually lose biometric responseand fatigue behavior. Then, an alternative strategy wasdeveloped to prove that nanostructuring CP Ti by SPDprocessing may become a novel and high-performanceapproach to enhance the mechanical properties of thismaterial to the next level.16­20) This strategy also has theadvantage of improving the biological response of the CPtitanium surface.21)

The earliest results on nanostructured CP Grade 4 Ti [C ­0.052%, O2 ­ 0.34%, Fe ­ 0.3%, N ­ 0.015%, Ti-bal. (wt.pct.)] were performed by Valiev et al. with the aim todevelop the material in the form of long-length rods withsuperior mechanical and biomedical properties for thefabrication of dental implants.22) Processing involved SPDtechnique by equal-channel angular pressing23) and furtherthermo-mechanical treatment (TMT) through forging anddrawing to improve the nanostructuring of 7-mm diameterand 3-m long bars. After combined SPD and TMT processinga large reduction in grain size was observed, in particular+Corresponding author, E-mail: ruslan.valiev@ugatu.su

Materials Transactions, Vol. 60, No. 7 (2019) pp. 1356 to 1366Special Issue on Severe Plastic Deformation for Nanomaterials with Advanced Functionality©2019 The Japan Institute of Metals and Materials OVERVIEW

from the 25 µm in the initial Ti rods to 150 nm of theprocessed one, as in Fig. 1. The selected area electrondiffraction (SAED) pattern, Fig. 1(c), illustrates a typical fornanoSPD processed materials picture when the grainboundaries in ultrafine grains are of predominantly high-angle type with increased internal stresses.4)

Rods of CP Ti produced by a continuous SPD method,known as ECAP-Conform, followed by drawing to producethe necessary length had a similar structure.20,24) Here, themain issue was to provide the formation of homogeneousultrafine-grained structure along the entire three-meter rodlengths for economical fabrication of implants and to developthe SPD technology for mass production of nanoTi.

Table 1 illustrates the advantages of mechanical propertiesin CP titanium after nanostructuring by ECAP and TMT.As is seen, the nanostructured titanium has 2 times higherstrength than the conventional CP titanium without anydrastic ductility reductions (to below 10% elongation tofailure) normally observed after rolling or drawing.

Fatigue testing for nanostructured and conventional CPtitanium conducted at room temperature in air was performedper ASTM E 466-96 at a load ratio R (rmin/rmax) = 0.1and loading frequency of 20Hz. As shown in Table 1, thefatigue strength of nanostructured CP titanium after one

million cycles is about two times higher than that ofconventional CP titanium and exceeds that of the Ti­6Al­4V alloy.15,25) Considerable improvement of fatigue proper-ties was also shown in the rods from nanostructured TiGrade 4 produced by ECAP-Conform and drawing.13,24) Thehigh strength of nanoTi allows development of smaller sizesof implants, which reduces the level of surgical intervention(see, also, Section 3).

Recent studies have shown that the nanostructured Ti afterSPD demonstrates the improvement of biological reactionon the surface as well. This was confirmed in a series ofexperiments through cytocompatibility tests using mousefibroblast tests.26­30)

Titanium is known for its very high biocompatibility as aresult of the protective oxide film, or titanium dioxide, TiO2,that forms naturally on its surface and provides a stablesurface on which a mineralized bone matrix can be set. Thisfilm is usually 50­100¡ thick and biologically inert, thus itprevents reaction between the metal and the surroundingbody environment.15)

The presence of ultrafine-grained structure and non-equilibrium strain-distorted grain boundaries in nanoTiproduced by SPD significantly increases the internal energyof the material4) and, as a result, this may considerably

(a) (b) (c)

Fig. 1 Microstructure of Grade 4 CP Ti before and after SPD processing: (a) the initial rod; (b), (c) after ECAP and TMT (Optical andelectron micrographs).

Table 1 Mechanical parameters of initial coarse-grained (CG) and nanostructured (NS) CP Grade 4 Ti.

Developing Nanostructured Metals for Manufacturing of Medical Implants with Improved Design and Biofunctionality 1357

change the morphology of oxide film. This might be due tothe fact that processing by SPD is typically favorable forcellular attachment to titanium with polished surfaces.21) Atthe same time, surface modification opens even morepossibilities for improvement of biomedical properties ofnanostructured titanium (see Section 4).

2.2 Titanium alloysCurrently among commonly used metallic materials in the

dental and orthopedic fields, titanium alloys such as Ti­6Al­4V (Ti64) and Ti­6Al­7Nb continue to be the most importantcomponents due to their high mechanical properties andrelatively good biocompatibility.15,31­34) However, aluminumand especially, vanadium are rather toxic elements andfurther reducing of the Young’s modulus of these alloys isalso a relevant challenge for today. Thus, there is a reasonablenecessity to develop a new generation of titanium alloyswith improved strength, lower Young’s modulus and betterbiocompatibility compared to Ti64.2,3) Close attention is paidto optimization of titanium alloying, in particular for thesystems Ti­Nb and Ti­Mo. At the same time, one of thenew approaches that may play a key role to provide theseimprovements is based on nanostructuring of titanium alloysby SPD techniques.12)

Recent studies progressively contributed to increasingmechanical and functional properties of titanium alloys usingtheir nanostructuring. Key results are described below.

In Refs.35­37) complex studies of the microstructureand mechanical properties of Ti­6Al­4V ELI (extra lowinterstitial alloys for medical applications) processed bySPD were conducted. The alloy was in a form of round rods40mm in diameter (Intrinsic Devices Company USA) andwith chemical composition as following: Ti ­ base, Al ­6.0%; V ­ 4.2%; Fe ­ 0.2%; C ­ 0.001%; O2 ­ 0.11%; N2 ­0.0025%; H2 ­ 0.002% (mass%). The two-phase alloy hadthe following microstructure in the as-received state: a grainsize of about 8 µm in a cross-section, 20 µm in alongitudinal section. According to the X-ray analysis, thecorresponding volume fractions of ¡ and ¢ phases wasabout 85% and 15%, respectively. The processing of the250-mm length rods was divided into two steps. At first, therods were subjected to ECAP at 600°C via route Bc andthen further extrusion with total strain 4.237) to produce therods 18mm in diameter and up to 300mm in length. Theextrusion was carried out at 300°C with the last pass atroom temperature for additional strengthening. Furthertreatment included annealing in the range of temperaturesfrom 200°C to 800°C for 1 hour and subsequent cooling inair.

TEM studies revealed that SPD intensifies grain refinementand leads to a complex UFG structure forming of the grainsand subgrains with a mean size of about 300 nm.

Figure 2 displays typical stress­strain curves for the CGand UFG alloy demonstrating that the alloy after grainrefinement by SPD undergoes considerable strengthening.Tensile elongation of the UFG alloy (curve 2) is reducedfrom 17% down to 9% in contrast to the material in theas-received state (curve 1). Figure 2 shows that strength andductility further improved (up to 12%) from subsequentannealing at 500°C, with uniform elongation of about 4%.

The results of tensile tests correspond accurately to themicrohardness measurement data (Fig. 3).

In accordance with Ref.37), ductility enhancement in theUFG alloy after annealing is obviously associated with suchfactors as decrease in internal elastic stresses and dislocationdensity. At the same time, the observed decay of metastable¢-phase during cooling from the annealing temperatureexplains additional strengthening of the alloy. Its volumefraction in the structure of the UFG alloy at 500°C can behigher than before annealing, as has been shown in Ref.38),using quenching from the annealing temperature. Thoughthere are no visible particles of any second phase, agingprocesses could cause the formation of grain boundarysegregations that may additionally increase the properties ofthe UFG alloy after annealing.39,40)

Investigations of fatigue properties of the Ti­6Al­4V ELIalloy with ultrafine grains revealed that high strength andenhanced ductility after SPD processing and additionalannealing at 500°C (1370MPa and 12%) resulted in fatiguelimit enhancement on the basis of 107 cycles up to 740MPain comparison with 600MPa in the initial coarse-grained(CG) state (Fig. 4).

The fatigue limit for the UFG Ti­6Al­4V alloy reported inRef.35) under the conditions of rotating bending was only

Fig. 2 Engineering stress­strain tensile curves of the Ti­6Al­4V ELI alloy:initial, coarse-grained state (1); UFG state before (2) and after annealing at500°C (3).

Fig. 3 Influence of annealing temperature on microhardness of the UFGTi­6Al­4V ELI alloy; annealing time is 1 h.

R.Z. Valiev, E.V. Parfenov and L.V. Parfenova1358

slightly higher than the earlier value in Refs.36,41), whichproves the fact that the level of fatigue properties may dependon the measurement technique.

Thus, the results show that high strength can be achieved inUFG Ti­6Al­4V ELI alloy through ECAP and additionalmechanical and thermal treatment. Moreover, it is possible tomanipulate the grain boundary structure and phase morphol-ogy in the UFG alloy by changing the SPD regimes andparticularly, such processing parameters as temperature, strainrate, strain, and consequently achieve the best combinationsof strength and ductility, as well as the improved fatigueendurance limit of up to 740MPa, well beyond the 600MPalevel measured in the coarse-grained alloy.

Another recent work42) is devoted to enhancement ofstrength and ductility of the Ti­6Al­7Nb alloy. If comparedto Ti­6Al­4V, the alloy is a better choice material for humanbody as it is less harmful. In addition it demonstrated ratherattractive properties after processing by ECAP with thermo-mechanical treatment when the formation of UFG structureled to higher strength (UTS = 1400MPa) and ductility(elongation 10%). These levels of properties are verypromising for the new design and fabrication of high-performance medical implants.

As indicated above, recent interest has been drawn totitanium alloys based on Ti­Mo and Ti­Nb systems withmainly the ¢ phase because the alloys have Young’s moduliin the range of 55­90GPa, and thus possess lower stressshielding.43­47) Plus, these Ti alloys contain only non-toxicelements such as Nb, Mo, Zr, and Ta. However, the singlephase ¢-Ti alloys that display the lowest Young’s modulusare commonly obtained after solution treatment and thus arerelatively soft. An ideal combination would be high strengthand low Young’s modulus, which is hardly true for thesematerials. Substantial strengthening can be achieved byageing treatments that induce a fine and uniform precipitationof ½ and ¡ phase components, but this inevitably increasesthe Young’s modulus of the alloy.43,44,48,49) Advancementsin the areas of dentistry and orthopedics called for newstrategies to develop ¢-Ti alloys with low Young’s modulusand high strength that are more suitable for such applications.

Recent developments deal with introducing SPD process-ing as a promising way to fabricate nanocrystalline ¢-Ti

alloys that should have simultaneously high strength, lowmodulus of elasticity and excellent biocompatibility.50­54)

Nanostructuring of the alloys leads to such desirablemechanical properties as higher strength resulting from grainrefinement and substructure55) and lower rigidity arising fromthe complete removal of the ½ phase and nanocrystallinestructure, plus surface modification contributes to improvedbiological responses. The nanocrystalline ¢-Ti alloys alsodisplay excellent in vitro biocompatibility, shown byenhanced cell attachment and proliferation.56) These novelnanocrystalline ¢-Ti alloys have high chances to meet thechallenge of next-generation implant material with significantprospects in load bearing biomedical applications.

2.3 Stainless steelsAustenitic stainless steels are also the most widely used

medical biomaterial due to excellent corrosion and oxidationresistance and good formability. However, low mechanicalstrength and poor anti-friction properties of these materialsare the critical obstacles for their application. In the last twodecades much attention has been drawn to strengthening thestainless steels and several approaches have been developed,including SPD processing.12)

As was said, austenitic stainless steels can be strengthenedby severe plastic deformation. For example, the strengthincrease from 515MPa to 1647MPa was demonstrated on316L stainless steel in Ref.57). Similarly, a yield strength of1460MPa in a duplex 32304 stainless steel after just 4 ECAPpasses was shown in Ref.58). Moreover, as was presented,59)

the nanostructured SPD 316L steel exhibited extremely highyield strength up to 2230MPa, which is the highest everreported value in literature for austenitic steels.

Plastic deformation has become an effective method toprocess stainless steel that are quite responsive to SPD,however the implementation of the SPD-processed stainlesssteels in practice has been slow. This is partially due to thefact that SPD causes apparent changes in microstructure ofstainless steels that need to be more accurately controlled.SPD readjusts the phase compositions from those normallyexpected in stainless steel. This occurs through mechanismsincluding stress-induced and strain-induced phase trans-formation, including the martensite formation. For example,strain-induced martensite was nucleated during ECAP of30160) and 304 stainless steels.61) SPD introduces nano-structural features such as nano-twins, micro-shear bands,very high dislocation densities and substructures. SPD alsochanges the formation and distribution of carbides. Thesenanostructural features may significantly influence on theannealing and recrystallization behaviors of stainless steelsand therefore their surface properties.62,63)

On the other hand, the surfaces of nanostructured stainlesssteel provide enhanced corrosion resistance64,65) and cellgrowth and proliferation.66,67) These results are encouragingindicators of the potential for nanostructured stainless steelsfor biomedical applications.

2.4 Magnesium alloysMagnesium is a biodegradable and bioresorbable material

with very light weight and, therefore, it is widely tested as apotential implant material.68­71) As the lightest of all light

Fig. 4 Fatigue test results of the samples made of CG and UFG alloy afterannealing at 500°C, 1 hour.

Developing Nanostructured Metals for Manufacturing of Medical Implants with Improved Design and Biofunctionality 1359

metal alloys used for structural applications (exceptberyllium) magnesium is an excellent choice to be used forengineering of medical devices when weight is a criticaldesign matter and the range of such applications may varyfrom wheelchairs and stretchers to surgical tools, vascularstents and orthopedic implants.71­73) However, the followingfour major limitations must be addressed for the traditionalMg alloys: limited strength, ductility, corrosion resistance andhighly anisotropic mechanical properties. But all four of theselimitations may be addressed mostly through nanostructuringby SPD processing.12,74,75)

The most interesting aspect of recent studies on improvingthe properties of magnesium alloys by SPD processingregards modifying their strength, ductility, and corrosionbehavior to satisfy the requirements for biomedicalapplications.71,75­78) The prospect of bioresorbable magne-sium implants has gained significant attention in the medicalcommunity, and has become the focus of extensivereviews.12,74,79)

Magnesium is a suitable candidate for stent applicationsbut pure metal is rarely used due to its low corrosionresistance. Nanostructuring of Mg-based alloys offers avariety of alternative ways and solutions to alloying fordesign and manufacturing of a magnesium stent. First, thecorrosion rates are subject to change depending on grain sizereduction. Hao et al.80) revealed that the corrosion rate inHank’s solution can be reduced by subjecting an AZ31 alloyto ECAP, however the obtained values were still not suitablefor stent applications. Hadzima et al.81) demonstratedimproved electrochemical properties in the AZ80 alloy aftercombined processing by ECAP and extrusion due to theformation of an ultrafine grain structure; thus it becamepossible to produce the polarization layers that remainedstable and resisted degradation up to 96 hours. Most recentstudies by Minárik et al.82) were focused on testing theelectrochemical characteristics of AE21 and AE42 alloysafter 8 passes of ECAP. As a result, the grain size wasreduced, thus increasing the corrosion rate in the alloy AE21owing to enhanced chemical activity at the grain boundaries.In contrast, the corrosion rate in the alloy AE42 after similarprocessing by ECAP was reduced. In the latter case, theeffect of a smaller grain size was overruled by the largereffect of increased uniformity of the spatial distribution ofalloying elements. Obviously, nanostructuring of magnesiumalloy for stent application is a complex task, when the effectsof processing on every particular alloy should be carefullyconsidered, which makes it even more challenging andattractive for further studies.

Significant improvement of strength and ductility ofmagnesium alloys by nanostructuring provides betterformability during stent processing and increases the in situexpandability and the force bearing capability of the insertednanostructured magnesium stents. A very high level ofproperties for bioabsorbable magnesium alloys have beenreported by Kutniy et al.83) and Dobatkin et al.75) for alloyWE43 and by Pachla et al.84) for AZ31, AZ 61, and AZ91alloys. It is necessary to outline and achieve suitablecombinations of mechanical properties and for this overallstent design factors that influence stent-host interactionsshould be considered.

3. Design and Fabrication of Miniaturized Implants

The superior mechanical properties of nanostructuredmetals enable the development of improved design formedical implants. Recently, we have studied two examples ofmaking and using these implants from nanoTi with premiumdesign for dentistry and orthopedics.13)

3.1 Nano Ti miniplatesChange of materials, such as the case with substituting

nanostructured CP Ti for CG Ti, leads to altering the designof devices and this is when a set of simple rules should betaken in account. Lately, the necessary calculations wereconducted to analyze the geometry of miniplates made ofnanostructured Ti for maxillofacial surgery.13,85)

A mini-plate made of CP Ti, as specified by ASTM F 67,was used by a “Conmet” company (Moscow, Russia) as thestarting point for redesigning the product dimensions formaking a nanostructured CP Ti mini-plate. The cross-sectionproperties of a new plate were computed using the estimatesof the fatigue endurance limit for coarse-grained Grade 4 Ti·f(CG) and nanostructured Grade 4 Ti ·f(NS).

Comparison of bending strength for mini-plates fromconventional CG Ti and nanostructured Ti was performed86,87)

because plates commonly support bending loads.15) Further,the fatigue strength of mini-plates was compared throughtesting with an ElectroPuls E3000 system.87) The numberof cycles to failure N was determined through cyclic 3mmdisplacements at 30Hz. Triplicate tests were completed.

Table 2 provides the estimation results for cross-sectionarea of the nano-Ti plate.85) The width and the diameterremain the same as in the standard item, whereas the platethickness alters from 0.9 to 0.7 (Fig. 5).

These experiments showed that the plate strength does notnecessarily decreases in the process of bending even whenthe cross-section area is reduced.

Bending tests were completed for the experimental valuesof the fatigue life of plates, as is shown in Fig. 6. Thestandard plates have sustained 17000 « 500 cycles and theredesigned plate made from nanostructured Ti could survivea larger number of cycles to failure (105000 « 800). Thisresult indicates that the plate from nano-Grade 4 Ti has itsbending strength significantly improved and thus, speaks ofits clear advantage over the standard item manufactured fromcoarse-grained Ti.

3.2 Dental thin implantsNumerous nanoimplantμ dental implants have been

produced from pure nanostructured Grade 4 Ti rodsprocessed by the ECAP-Conform on CNC machines indiameters of 2.0mm, 2.4mm and 3.5mm with the intraossealpart length of 8, 10, 12 and 14mm by the company“Timplant” s.r.o., Czech Republic over the last years (http://www.timplant.cz/en/) (see also Ref. 13)). The implants arecharacterized by an etched threaded tapered intraosseal partwith a polished gingival part and prosthetics cone top withinterior thread above it, and with anti-rotation crown element.High primary stability is achieved by an enhanced threaddesign with self-drilling thread groove. Special etchingprovides the surface roughness (see Section 4 for details).

R.Z. Valiev, E.V. Parfenov and L.V. Parfenova1360

Nano-CP Ti is responsible for having no toxic alloyingelements (such as Vor Al) or allergens (such as Ni, Co, or Cr)and it is clearly attractive for the production of thin implantsowing to its high strength. Statistical observation completedover two years by five surgeon dentists both from state-owned and privately-run dental surgeries in the CzechRepublic88) demonstrated high clinical performance of2.4mm Nanoimplantsμ.

4. Surface Modification of Nanometals for ImplantApplications

Surface properties are critical for medical implants andtheir modification has proved to accelerate osseointegration.In particular, pure Ti is bionert material meaning that whenplaced in the human body it has minimal interaction withsurrounding tissue, including the human bone.20) Application

of SPD processing to achieve nano-sized grains in CP Tiallows various types of bone-forming cells to adhere andproliferate with better efficiency and this was demonstrated innumerous studies.20,30,89­91) Additional surface modificationmay further contribute to better bioactive performance ofimplants made of nano Ti. Recently, two main approachesgained significant interest in dental implant surfacemodification: chemical etching and deposition of bioactivecoatings.13,92­98)

The topography of etched surfaces is strongly determinedby etching solution and etching time. Different solutions,such as acidic (H2SO4/H2O2) or basic (NH4OH/H2O2)Piranha solutions can be used for etching of CP Ti97)

resulting in different surface topographies. The surfacetopography was found to be clearly modified after varyingetching time and the effect was more pronounced in the nanoTi, as it has been very recently demonstrated in Fig. 7.97)

Biocompatible coatings can also efficiently make the nanoTi implants integrate with the human bone.95,96) Presently, theresearch into synthesis of biocompatible coatings integratingthe inorganic (Ca-, P- containing phases) and organic(biologically active and bioinert molecules) components ontitanium implants appears to be topical state of the art.99,100)

Plasma electrolytic oxidation (PEO) offers excellentpossibilities for developing Ca-, P- containing biocompatiblecoatings on the surface of implants both for orthopedics andtraumatology applications.101,102) The majority of implantmaterials, both conventional as titanium, and prospective asmagnesium and zirconium, belong to a group of so-calledvalve metals that can be easily coated with the PEOtechnique.103,104) Currently, PEO is extensively researched

Fig. 5 Image of a mini plate with six holes made of nanostructuredGrade 4 Ti.

Fig. 6 Fatigue life of the standard plate and redesigned plate from nano-Ti.

Fig. 7 Surface of CG and NS samples of Grade 4 Ti after mechanicalpolishing and etching in the mixture of acids 30% HNO3 + 3% HF+H2Ofor 20 minutes: (a) CG Ti surface; (b) nano-Ti surface. SEM images.

Table 2 Sizes of a base plate from CG and NS CP titanium.

Developing Nanostructured Metals for Manufacturing of Medical Implants with Improved Design and Biofunctionality 1361

for development of biocompatible and bioactive coatings onTi, Mg, Zr alloys, including nanostructured.13,98,105,106) ThePEO process is an expansion of the traditional anodizing intothe high voltages up to 600V; these voltages promotemicrodischarges within the coating; this results in itsresolidifying and intensive growth.107­109) The coatingsobtained by this method contain stable titania (rutile andanatase) tightly attached to the surface because of the processmechanism which includes electrochemical oxidation andnumerous melting and crystallizing events at the micro-discharge sites (Fig. 8(a)).110,111) This mechanism providesthe surface morphology with regulated roughness andporosity (Fig. 8(b), (c)) welcoming the osteoblast adhesionin the human body.112,113) As it was shown recently, nano Ticoated with the PEO technique has finer structure, containsmore biocompatible compounds and shows higher celladhesion compared to the coating on CG Ti.98)

For the orthopedic applications, the PEO coating openspossibilities to develop an “ideal coating”. This coatingprovides enhanced biocompatibility due to following thebiomimetic approach at physical, chemical and biologicallevels.98,114) At physical level, a gradual change of theelasticity modulus from the metallic implant to the bone isachieved because the wide network of the pores forms afractal-like structure, with the pore size increasing to the topof the coating.112) Unlike other methods, for the PEO thereis no need to create a surface with high roughness.101,115) Thehigh surface area of the porous PEO coating promotesosteoblast attachment on the implant surface,116) because thesponge-like coating morphology exhibits the surface rough-ness (Ra) from 1 to 5 µm and rounded pores with a diameterfrom 0.1 to 10 µm; this provides the sites for mechanicalattachment of the cells with protein pseudopodia.117,118)

Adhesion of the PEO coatings is higher than that of theother coating types.119) At the chemical level, by applyingvarying pulse polarity during PEO, it is possible toincorporate the anions and cations of the electrolyte intothe coating; this provides Ca- and P- containing bioactivecrystalline phases within the coating: hydroxyapatite,tricalcium phosphate, tetra calcium phosphate, perovskite.Since the early works,120) the PEO coating technology forimplant materials has been significantly developed so thatnow these coatings incorporate species like silver providinganti-bacterial response and compounds like hydroxyapatitestimulating the bone growth.116,121) At the biological level,the biomimetic properties can be introduced by applying a

bioactive organic top coat into the PEO pores. For example,peptide LL-37 in combination with phospholipids used withPEO coatings helped to achieve antimicrobial activity fortitanium implants.122) A recent study of nanostructuredtitanium subjected to PEO and further modification withRGD containing peptide showed significant improvementof all the crucial implant properties: strength, corrosionresistance and biocompatibility.98) Therefore, the researchinto the development of the biocompatible coatings onnanostructured implants by PEO is an actual problem of themodern engineering and technologies.

Further advances in the PEO treatments to develop abiomimetic coating can be summarized as shown in Fig. 9.This includes changes in electrical regimes, electrolytecomposition, and applying post treatments. As follows fromspecific studies, pulsed bipolar treatment does not necessarilyprovide the best protective properties for the coatings. Thisconcerns Mg and Zr.123,124) Also, the electrolyte optimizationis also not a straightforward technique. For example, MgPEO in early studies was performed in fluoride containingelectrolytes;125,126) this is not an environmentally friendlyapproach. Currently, the non-fluoride electrolyte wasproposed.127) One of the major drawbacks of these electro-lytes is the application of very low soluble components, e.g.Ca3PO4 or Ca(OH)2; this makes the electrolytes cloudy andunstable. Therefore, using complex forming agents, e.g.EDTA, transfers the electrolytes into colloids with higherstability.113,128) An important aspect of the PEO coatingbioactivity increase is the development of higher hydrox-yapatite (HAp) content. Usually, Ca-, P- containing phasesin the PEO coating have a various crystalline structure, andalso a significant amount of amorphous phase is present.However, application of a hydrothermal post-treatmentprovides recrystallization of the amorphous phase andformation of the HAp crystallites.119) Electrophoreticdeposition is another surface modification method whichcan be coupled with the PEO to form a duplex process. Themechanism of electrophoresis coupled with the PEO canhelp to enrich the coating with the nanoparticles that arepre-charged before the process runs.129) PEO coupled withelectrophoretic deposition (PEO-EPD) is gaining muchattention for producing composite coatings with betterproperties than PEO.130) As a result, the properties of PEOcoatings on Al, Mg and Ti substrate can be improved byadding nanoparticles such as HAp, ZrO2, Al2O3, TiO2, andCeO2.131)

(a) (b) (c)

Fig. 8 Microdischarge appearance during PEO (a); PEO biocompatible coating on nanostructured Ti, top view (b) and cross-section (c).

R.Z. Valiev, E.V. Parfenov and L.V. Parfenova1362

Since the PEO coatings always have a porous structure,as follows from its mechanism,132) the corrosion resistanceand bioactive properties can be further improved by a poresealing treatments with an organic compound top coating.Superhydrophobic composite PEO-coatings on titanium andmagnesium obtained by application of polytetrafluoro-ethylene (UPTFE) for the PEO coating pore filling reducesthe corrosion rate by 4 orders of magnitude and more; thishelps to control inflammatory response of a body.133­135) Byusing polyethylene glycol methacrylate (PEGMA), thesuperhydrofobization of coatings was achieved to providegood hemocompatibility.136) A study conducted for the PEOcoating on titanium with the functionalization by chitosanshowed an improvement of the corrosion properties.137)

Significant progress in improving the corrosion propertiesof magnesium implants, including nanostructured, has beenachieved with the creation of combined coatings based onPEO and biocompatible polymers - polyesters or polysac-charides. Among synthetic biocompatible and bioresorbablepolymers, aliphatic polyesters, such as polylactic acid (PLA),poly-lacto-glycolic acid (PLGA), polycaprolactone (PCL),polyethyleneimine (PEI) and many other polymers are ofthe most interest.138) These polymeric materials provide veryattractive coating options for PEO modified coarse-grainedand nanostructured Mg and its alloys, since they allowcontrolling the initial dissolution rate of the biodegradableimplant; this depends, among other things, on the nature andmolecular weight of the polymer. The plasma electrolyticoxidation of the magnesium surface creates a porous surfacethat improves the adhesion of polyesters and significantlydecreases the corrosion rate.139­142) An in vivo study showedthat this method of the surface modification providedsufficient time for bone healing and promotion of new bonegrowth.143) Improved corrosion resistance of magnesium afterits modification by PEO and non-toxic organic additives -hexamethylenetetramine and mannitol was shown as well.144)

That makes these coatings promising for biomedicalapplications on nanostructured Mg implants. Hydrophilicsurface was obtained by PEO with a natural polysaccharideshyaluronic acid (HA) and carboxymethylcellulose (CMC) inorder to improve bonding function.145) The PEO treatmentimproves the corrosion resistance by inducing chemical

bonding with the biopolymer and sealing the bending of theporous oxide. The combination of PEO with HA exhibitedthe best retentive ability after implantation. Moreover, theintroduction of HA-CMC cross-linked hydrogel into the PEOlayer provided the self-healing of localized damage andstable osteocytes in long term bone regeneration.

Therefore, the direction of filling the PEO pores onnanostructured metal implants either with the nanoparticlesor the bioactive organic molecules follows the biomimeticapproach to the development of advanced coatings, and asignificant scientific outcome is expected in this field.

5. Conclusions

Thus, the results of recent studies presented in thisoverview convincingly attest to the fact that metallicbiomaterials (Ti and Ti alloys, stainless steels and other)after their nanostructuring by severe plastic deformationtechniques demonstrate improved mechanical and functionalproperties, and this accounts for the considerable interest intheir medical applications. The latter is also confirmed by theproceedings of the International Workshop on Giant StrainingProcess for Advanced Materials (GSAM2018) held in 2018at Kyushu University (JAPAN) and devoted to thesignificance of severe plastic deformation for the productionof biomedical and biocompatible materials.146)

Improved mechanical properties of nanomaterials createsolid opportunities for manufacturing of medical implantswith improved design and miniaturized devices. Theexamples of first successful applications of dental andmaxillofacial nanoimplants made of nanostructured titaniumare considered and discussed in the overview. The paper alsohighlights the works on the development of continuousSPD processing, in particular, ECAP-Conform technique,designed for mass production of nanotitanium and othernanometals.

The study of biomedical properties of SPD-processednanometals is a relatively new task because nanostructuringintroduces certain advanced features in the materials bio-logical response. At the same time, the results of recentstudies on surface modification, including chemical etchingand deposition of bioactive coatings, make it a promising

Fig. 9 Further advances in the PEO treatments for biomedical implants.

Developing Nanostructured Metals for Manufacturing of Medical Implants with Improved Design and Biofunctionality 1363

approach for the development of advanced medical implantsand devices with improved design and biofunctionality.

Acknowledgments

The authors (RZV) gratefully acknowledge the financialsupport from Russian Science Foundation (project No. 19-49-02003), and through the RFBR project 17-03-01042(EVP). We would like to sincerely thank all our colleaguescited in the list of references and, in particular, Prof. TerryLowe for numerous joint studies on the subject.

REFERENCES

1) T. Hanawa: Sci. Technol. Adv. Mater. 13 (2012) 064102.2) T. Hanawa: Metals for Biomedical Devices, (Woodhead Publishing

Limited, Oxford, 2010) pp. 3­24.3) F.H. Froes and M. Qian: Titanium in Medical and Dental

Applications, (Woodhead Publishing, Duxford, UK, 2018) p. 630.4) R.Z. Valiev, R.K. Islamgaliev and I.V. Alexandrov: Prog. Mater. Sci.

45 (2000) 103­189.5) R.Z. Valiev, Y. Estrin, Z. Horita, T.G. Langdon, M.J. Zehetbauer and

Y.T. Zhu: JOM 68 (2016) 1216­1226.6) R.Z. Valiev, Y. Estrin, Z. Horita, T.G. Langdon, M.J. Zehetbauer and

Y.T. Zhu: Mater. Res. Lett. 4 (2016) 1­21.7) S.H. Whang: Nanostructured Metals and Alloys: Processing, Micro-

structure, Mechanical Properties and Applications, (WoodheadPublishing Limited, Oxford, 2011).

8) A. Rosochowski: Severe Plastic Deformation Technology, (WhittlesPublishing, Scotland, UK, 2017) p. 272.

9) Y. Estrin and A. Vinogradov: Acta Mater. 61 (2013) 782­817.10) Y. Takizawa, T. Masuda, K. Fujimitsu, T. Kajita, K. Watanabe, M.

Yumoto, Y. Otagiri and Z. Horita: Metall. Mater. Trans. A 47 (2016)4669­4681.

11) E.I. Fakhretdinova, G.I. Raab and R.Z. Valiev: Adv. Eng. Mater. 17(2015) 1723­1727.

12) T.C. Lowe and R.Z. Valiev: Advanced biomaterials and biodevices,ed. by A. Tiwari and A.N. Nordin, (Wiley-Scrivener Publ., USA,2014) pp. 3­52.

13) R.Z. Valiev, I. Sabirov, E.G. Zemtsova, E.V. Parfenov, L. Dluhoš andT.C. Lowe: Titanium in Medical and Dental Applications, ed. by F.Froes and M. Qian, (Woodhead Publishing, Duxford, UK, 2018)pp. 393­418.

14) E.G. Zemtsova, A.Y. Arbenin, R.Z. Valiev and V.M. Smirnov:Titanium in Medical and Dental Applications, ed. by F. Froes and M.Qian, (Woodhead Publishing, Duxford, UK, 2018) pp. 115­146.

15) D.M. Brunette, P. Tengvall, M. Textor and P. Thomsen: Titanium inMed, (Springer-Verlag Berlin, Heidelberg, 2003).

16) R.Z. Valiev: Nat. Mater. 3 (2004) 511­516.17) V.V. Stolyarov, V.V. Latysh, R.Z. Valiev, Y.T. Zhu and T.C. Lowe:

Investigations and Appl. of Severe Plastic Deformation, (KluwerAcademic Publishers, 2000).

18) Y.T. Zhu, T.C. Lowe, R.Z. Valiev, V.V. Stolyarov, V.V. Latysh and G.I.Raab: U.S Patent 6399 215, 2002.

19) V.V. Latysh, I.P. Semenova, G.H. Salimgareeva, I.V. Kandarov, Y.T.Zhu, T.C. Lowe and R.Z. Valiev: Mater. Sci. Forum 503­504 (2006)763.

20) D.V. Gunderov, A.V. Polyakov, I.P. Semenova, G.I. Raab, A.A.Churakova, E.I. Gimaltdinova, I. Sabirov, J. Segurado, V.D. Sitdikov,I.V. Alexandrov, N.A. Enikeev and R.Z. Valiev: Mater. Sci. Eng. A562 (2013) 128.

21) Y. Estrin, R. Lapovok, A.E. Medvedev, C. Kasper, E. Ivanova andT.C. Lowe: Titanium in Medical and Dental Applications, ed. by F.Froes and M. Qian, (Woodhead Publishing, Duxford, UK, 2018)pp. 419­454.

22) R.Z. Valiev, I.P. Semenova, V.V. Latysh, H. Rack, T.C. Lowe, J.Petruzelka, L. Dluhos, D. Hrusak and J. Sochova: Adv. Eng. Mater. 10(2008) B15­B17.

23) R.Z. Valiev and T.G. Langdon: Prog. Mater. Sci. 51 (2006) 881­981.24) L. Mishnaevsky, Jr. et al.: Mater. Sci. Eng. R 81 (2014) 1.25) R. Boyer, G. Welsch and E. Collings: Mater. Properties Handbook:

Titanium Alloys, (ASM International, 1998).26) J. Petruželka, L. Dluhoš, D. Hrušák and J. Sochová, Sb. Ved. Pr. Vys.

Šk. bánské ­ Tech. Univ. Ostrava. 2006, roc. LII. c.1. cl. 1517. ISSN1210-0471, 177.

27) S. Faghihi, A.P. Zhilyaev, J.A. Szpunar, F. Azari, H. Vali and M.Tabrizian: Adv. Mater. 19 (2007) 1069.

28) S. Faghihi, F. Azari, A.P. Zhilyaev, J.A. Szpunar, H. Vali and M.Tabrizian: Biomater. 28 (2007) 3887.

29) Y. Estrin: Acta Biomater. 7 (2011) 900­906.30) F.L. Nie, Y.F. Zheng, S.C. Wei, D.S. Wang, Z.T. Yu, G.K.

Salimgareeva, A.V. Polyakov and R.Z. Valiev: J. Biomed. Mater.Res. Part A 101 (2013) 1694­1707.

31) M. Geetha, A.K. Singh, R. Asokamani and A.K. Gogia: Prog. Mater.Sci. 54 (2009) 397­425.

32) K.I. Wapner: Clin. Orthop. Relat. Res. (1991) 12­20.33) M. Nakai, M. Niinomi, T. Akahori, N. Ohtsu, H. Nishimura, H. Toda,

H. Fukui and M. Ogawa: Mater. Sci. Eng. A 486 (2008) 193­201.34) K. Xie, Y. Wang, Y. Zhao, L. Chang, G. Wang, Z. Chen, Y. Cao, X.

Liao, E. Lavernia, R. Valiev, B. Sarrafpour, H. Zoellner and S. Ringer:Mater. Sci. Eng. C 33 (2013) 3530­3536.

35) I. Semenova, E. Yakushina, V. Nurgaleeva and R. Valiev: Int. J. Mat.Res. 100 (2009) 1691­1696.

36) L. Saitova, H. Hoeppel, M. Goeken, I. Semenova and R. Valiev: Int. J.Fatigue 31 (2009) 322­331.

37) I.P. Semenova, L.R. Saitova, G.I. Raab, A.I. Korshunov, Y.T. Zhu,T.C. Lowe and R.Z. Valiev: Mater. Sci. Forum 503­504 (2006) 757­762.

38) H.J. Rack, J. Qazi, L. Allard and R. Valiev: Mater. Sci. Forum 584­586 (2008) 893­898.

39) R.Z. Valiev, M.Yu. Murashkin, E.V. Bobruk and G.I. Raab: Mater.Trans. 50 (2009) 87­91.

40) G. Nurislamova, X. Sauvage, M. Murashkin, R. Islamgaliev and R.Valiev: Philos. Mag. Lett. 88 (2008) 459­466.

41) S. Zherebtsov, G. Salishchev, R. Galeyev and K. Maekawa: Mater.Trans. 46 (2005) 2020­2025.

42) V. Polyakova, I. Semenova and R. Valiev: Mater. Sci. Forum 667­669(2011) 943­948.

43) M. Niinomi: Biomaterials 24 (2003) 2673­2683.44) M. Niinomi: J. Mech. Behav. Biomed. Mater. 1 (2008) 30­42.45) D. Raabe, B. Sander, M. Friak, D. Ma and J. Neugebauer: Acta Mater.

55 (2007) 4475­4487.46) Y.L. Hao, S.J. Li, S.Y. Sun, C.Y. Zheng and R. Yang: Acta Biomater. 3

(2007) 277­286.47) F.Q. Hou, S.J. Li, Y.L. Hao and R. Yang: Scr. Mater. 63 (2010) 54­57.48) W.F. Ho: J. Med. Biol. Eng. 28 (2008) 47­54.49) M. Niinomi, M. Nakai and J. Hieda: Acta Biomater. 8 (2012) 3888­

3903.50) W. Xu, X. Wu, R.B. Figueiredo, M. Stoica, M. Calin, J. Eckert, T.G.

Langdon and K. Xia: Int. J. Mater. Res. 100 (2009) 1662­1667.51) H. Yilmazer, M. Niinomi, M. Nakai, K. Cho, J. Hieda, Y. Todaka and

T. Miyazaki: Mater. Sci. Eng. C 33 (2013) 2499­2507.52) A. Zafari, X.S. Wei, W. Xu and K. Xia: Acta Mater. 97 (2015) 146­

155.53) W. Xu, X. Wu, M. Calin, M. Stoica, J. Eckert and K. Xia: Scr. Mater.

60 (2009) 1012­1015.54) A.V. Polyakov, I.P. Semenova, E. Ivanov and R.Z. Valiev: IOP Conf.

Ser.: Mater. Sci. Eng. 461 (2018) 012077.55) R.Z. Valiev: Mater. Trans. 55 (2014) 13­18.56) J. Stráský, M. Janeĉek, I. Semenova, J. Čížek, K. Bartha, P. Harcuba,

V. Polyakova and S. Gatina: Titanium in Medical and DentalApplications, ed. by F. Froes and M. Qian, (Woodhead Publishing,Duxford, UK, 2018) pp. 455­475.

57) Y. Idell et al.: Scr. Mater. 68 (2013) 667­670.58) L. Chen et al.: Mater. Sci. Eng. A 551 (2012) 154­159.59) H. Wang, I. Shuro, M. Umemoto, H.-H. Kuo and Y. Todaka: Mater.

Sci. Eng. A 556 (2012) 906­910.60) C.X. Huang et al.: Metall. Mater. Trans. A 42 (2011) 2061­2071.61) G. Yang and F. Yin: Nanomaterials by Severe Plastic Deformation:

R.Z. Valiev, E.V. Parfenov and L.V. Parfenova1364

Nanospd5, Pts 1 and 2, ed. by J.T. Wang, R.B. Figueiredo and T.G.Langdon, (2011) pp. 879­884.

62) A.T. Krawczynska, M. Lewandowska and K.J. Kurzydlowski:Nanomaterials by Severe Plastic Deformation IV, Pts 1 and 2, ed.by Y. Estrin and H.J. Maier, (2008) pp. 966­970.

63) A.T. Krawczynska et al.: Phys. Status Solidi C 7 (2010) 1380­1383.64) Z.J. Zheng et al.: Corros. Sci. 54 (2012) 60­67.65) X. Han et al.: Acta Metall. Sin. 49 (2013) 265­270.66) F. Nie et al.: Nanomaterials by Severe Plastic Deformation:

Nanospd5, Pts 1 and 2, ed. by J.T. Wang, R.B. Figueiredo and T.G.Langdon, (2011) pp. 1113­1118.

67) R.D.K. Misra et al.: Acta Biomater. 9 (2013) 6245­6258.68) S. Virtanen: Mater. Sci. Eng. B 176 (2011) 1600­1608.69) A. Lafont and Y. Yang: The Lancet 387(10013) (2016) 3­4.70) D. Vojtech, H. Cizova and K. Volenec: Kov. Mater. 44 (2006) 211­

223.71) H.S. Brar et al.: JOM 61(9) (2009) 31­34.72) A.C. Haenzi, A.S. Sologubenko and P.J. Uggowitzer: Int. J. Mater.

Res. 100 (2009) 1127­1136.73) Y.F. Zheng, X.N. Gu and F. White: Mater. Sci. Eng. R 77 (2014) 1­34.74) K.U. Kainer et al.: Nanostructured Metals: Fundamentals to

Applications, ed. by J.C. Grivel et al., (2009) pp. 81­99.75) S.V. Dobatkin et al.: IOP Conf. Ser.: Mater. Sci. Eng. 194 (2017)

012004.76) D. Vojtich, H. Elova and K. Volenec: Met. Mater. 44 (2006) 206­219.77) R. Yibin et al.: Key Eng. Mater. 342­343 (2007) 601­604.78) J. Yang, F. Cui and I.S. Lee: Ann. Biomed. Eng. 39 (2011) 1857­

1871.79) M.P. Staiger et al.: Biomater. 27 (2006) 1728­1734.80) W. Hao et al.: Adv. Eng. Mater. 9 (2007) 967­972.81) B. Hadzima: Nanomaterials by Severe Plastic Deformation IV, Pts 1

and 2, ed. by Y. Estrin and H.J. Maier, (2008) pp. 994­999.82) P. Minarik, R. Kral and M. Janecek: Appl. Surf. Sci. 281 (2013) 44­

48.83) K.V. Kutniy et al.: Mater. Und Werkst. 40 (2009) 242­246.84) W. Pachla et al.: Int. J. Mater. Res. 103 (2012) 580­589.85) I.P. Semenova, G.V. Klevtsov, N.A. Klevtsova, G.S. Dyakonov, A.A.

Matchin and R.Z. Valiev: Adv. Eng. Mater. 18 (2016) 1216­1224.86) ISO 14602 Non-active surgical implants-Implants for Osteosynthesis

particular requirements.87) http://www.instron.com/en/testing-solutions/by-test-type/simple-cyclic/

orthopaedic-micro-implants88) A.V. Polyakov, L. Dluhos, G.S. Dyakonov, G.I. Raab and R.Z. Valiev:

Adv. Eng. Mater. 17 (2015) 1869­1875.89) S. Bagherifard, R. Ghelichi, A. Khademhosseini and M. Guagliano:

ACS Appl. Mater. Interfaces 6 (2014) 7963­7985.90) J.W. Park, Y.J. Kim, C.H. Park, D.H. Lee, Y.G. Ko, J.H. Jang and C.S.

Lee: Acta Biomater. 5 (2009) 3272­3280.91) M. Lai, K. Cai, Y. Hu, X. Yang and Q. Liu: Colloids Surf. B

Biointerfaces 97 (2012) 211­220.92) A.V. Polyakov, G.S. Dyakonov, I.P. Semenova, G.I. Raab, L. Dluhos

and R.Z. Valiev: Adv. Biomater. Dev. Med. 2 (2015) 63­69.93) Z.Q. Yao, Y. Ivanisenko, T. Diemant, A. Caron, A. Chuvilin, J.Z.

Jiang, R.Z. Valiev, M. Qi and H.J. Fecht: Acta Biomater. 6 (2010)2816­2825.

94) E.G. Zemtsova, A.Y. Arbenin, R.Z. Valiev, E.V. Orekhov, V.G.Semenov and V.M. Smirnov: Surf. Mater. 9 (2016) 1010.

95) D.V. Nazarov, E.G. Zemtsova, R.Z. Valiev and V.M. Smirnov:Materials 8 (2015) 8366­8377.

96) M.H. Shin, S.M. Baek, A.V. Polyakov, I.P. Semenova, R.Z. Valiev,W.B. Hwang, S.K. Hahn and H.S. Kim: Sci. Rep. 8 (2018) 9907.

97) D.V. Nazarov, E.G. Zemtsova, A.Yu. Solokhin, R.Z. Valiev and V.M.Smirnov: Nanomater. 7 (2017) 15.

98) E.V. Parfenov, L.V. Parfenova, G.S. Dyakonov, K.V. Danilko, V.R.Mukaeva, R.G. Farrakhov, E.S. Lukina and R.Z. Valiev: Surf. Coat.Technol. 357 (2019) 669­683.

99) S.V. Dorozhkin: Mater. Sci. Eng. C 55 (2015) 272­326.100) S. Wu, X. Liu, K.W.K. Yeung, C. Liu and X. Yang: Mater. Sci. Eng. R

80 (2014) 1­36.101) M. Mohedano, R. Guzman, R. Arrabal, J.L. Lõpez Lacomba and E.

Matykina: J. Biomed. Mater. Res. Part B Appl. Biomater. 101 (2013)

1524­1537.102) M.V. Diamanti, B. Del Curto and M. Pedeferri: J. Appl. Biomater.

Biomech. 9 (2011) 55­69.103) A.L. Yerokhin, X. Nie, A. Leyland, A. Matthews and S.J. Dowey:

Surf. Coat. Technol. 122 (1999) 73­93.104) F.C. Walsh, C.T.J. Low, R.J.K. Wood, K.T. Stevens, J. Archer, A.R.

Poeton and A. Ryder: Trans. Inst. Met. Fin. 87 (2009) 122­135.105) Y. Wang, H. Yu, C. Chen and Z. Zhao: Mater. Des. 85 (2015) 640­

652.106) A. Nominé, J. Martin, C. Noël, G. Henrion, T. Belmonte, I.V. Bardin

and P. Lukeš: Langmuir 32 (2016) 1405­1409.107) E.V. Parfenov, A. Yerokhin, R.R. Nevyantseva, M.V. Gorbatkov, C.J.

Liang and A. Matthews: Surf. Coat. Technol. 269 (2015) 2­22.108) V.I. Kalita, A.I. Mamaev, V.A. Mamaeva, D.A. Malanin, D.I. Komlev,

A.G. Gnedovets, V.V. Novochadov, V.S. Komlev and A.A. Radyuk:Inorg. Mater.: Appl. Res. 7 (2016) 376­387.

109) A. Nominé, S.C. Troughton, A.V. Nominé, G. Henrion and T.W.Clyne: Surf. Coat. Technol. 269 (2015) 125­130.

110) E.V. Parfenov, A. Yerokhin and A. Matthews: Surf. Coat. Technol.203 (2009) 2896­2904.

111) H. Sharifi, M. Aliofkhazraei, G.B. Darband and S. Shrestha: Surf.Rev. Lett. 25 (2018) 1830004.

112) A. Yerokhin, E.V. Parfenov and A. Matthews: Surf. Coat. Technol.301 (2016) 54­62.

113) O.P. Terleeva, A.I. Slonova, I.V. Mironov, A.B. Rogov and Y.P.Sharkeev: Surf. Coat. Technol. 307 (2016) 1265­1273.

114) Y. Su, C. Luo, Z. Zhang, H. Hermawan, D. Zhu, J. Huang, Y. Liang,G. Li and L. Ren: J. Mech. Behav. Biomed. Mater. 77 (2018) 90­105.

115) O. Jung, R. Smeets, A. Kopp, D. Porchetta, P. Hiester, M. Heiland,R.E. Friedrich, C. Precht, H. Hanken, A. Gröbe and P. Hartjen: InVivo 30 (2016) 27­33.

116) W.K. Yeung, G.C. Reilly, A. Matthews and A. Yerokhin: J. Biomed.Mater. Res. Part B 101 (2013) 939­949.

117) K. Anselme and M. Bigerelle: Int. Mater. Rev. 56 (2011) 243­266.118) F. Variola, F. Vetrone, L. Richert, P. Jedrzejowski, J.-H. Yi, S. Zalzal,

S. Clair, A. Sarkissian, D.F. Perepichka, J.D. Wuest, F. Rosei and A.Nanci: Small 5 (2009) 996­1006.

119) A.R. Rafieerad, M.R. Ashra, R. Mahmoodian and A.R. Bushroa:Mater. Sci. Eng. C 57 (2015) 397­413.

120) A.L. Yerokhin, X. Nie, A. Leyland and A. Matthews: Surf. Coat.Technol. 130 (2000) 195­206.

121) K. Venkateswarlu, N. Rameshbabu, A. Chandra Bose, V. Muthupandi,S. Subramanian, D. Mubarakali and N. Thajuddin: Ceram. Int. 38(2012) 731­740.

122) Y. He, Y. Zhang, X. Shen, B. Tao, J. Liu, Z. Yuan and K. Cai: ColloidsSurf. B Biointerfaces 170 (2018) 54­63.

123) Y. Gao, A. Yerokhin and A. Matthews: Appl. Surf. Sci. 316 (2014)558­567.

124) R.G. Farrakhov, V.R. Mukaeva, A.R. Fatkullin, M.V. Gorbatkov, P.V.Tarasov, D.M. Lazarev, N. Ramesh Babu and E.V. Parfenov: IOPConf. Ser.: Mater. Sci. Eng. 292 (2018) 012006.

125) H. Luo, Q. Cai, J. He and B. Wei: Current Appl. Phys. 9 (2009) 1341­1346.

126) A.S. Gnedenkov, S.L. Sinebryukhov, D.V. Mashtalyar and S.V.Gnedenkov: Corros. Sci. 102 (2016) 348­354.

127) Y. Gao, A. Yerokhin, E. Parfenov and A. Matthews: Electrochim. Acta149 (2014) 218­230.

128) A. Santos-Coquillat, R. Gonzalez Tenorio, M. Mohedano, E.Martinez-Campos, R. Arrabal and E. Matykina: Appl. Surf. Sci. 454(2018) 157­172.

129) D. Sreekanth and N. Rameshbabu: Mater. Lett. 68 (2012) 439­442.130) A. Sukumaran, H. Sampatirao, R. Balasubramanian, E. Parfenov, V.

Mukaeva and R. Nagumothu: Trans. Indian Inst. Met. 71 (2018)1699­1713.

131) X. Lu, M. Mohedano, C. Blawert, E. Matykina, R. Arrabal, K.U.Kainer and M.L. Zheludkevich: Surf. Coat. Technol. 307 (2016)1165­1182.

132) A.L. Yerokhin, L.O. Snizhko, N.L. Gurevina, A. Leyland, A.Pilkington and A. Matthews: J. Phys. D 36 (2003) 2110­2120.

133) T.S. Zaporozhets, A.V. Puz’, S.L. Sinebryukhov, S.V. Gnedenkov, T.P.Smolina and N.N. Besednova: Bull. Exp. Biol. Med. 162 (2017) 366­

Developing Nanostructured Metals for Manufacturing of Medical Implants with Improved Design and Biofunctionality 1365

369.134) S.V. Gnedenkov, S.L. Sinebryukhov, A.V. Puz, V.S. Egorkin and R.E.

Kostiv: Biomed. Mater. Eng. 27 (2016) 551­560.135) S.V. Gnedenkov, S.L. Sinebryukhov, A.G. Zavidnaya, V.S. Egorkin,

A.V. Puz’, D.V. Mashtalyar, V.I. Sergienko, A.L. Yerokhin and A.Matthews: J. Taiwan Inst. Chem. Eng. 45 (2014) 3104­3109.

136) Y. Chen, G. Yan, X. Wang, H. Qian, J. Yi, L. Huang and P. Liu: Surf.Coat. Technol. 269 (2015) 191­199.

137) M.P. Neupane, I.S. Park and M.H. Lee: Thin Solid Films 550 (2014)268­271.

138) J.C. Middleton and A.J. Tipton: Biomaterials 21 (2000) 2335­2346.139) L.-H. Li, T.S.N. Sankara Narayanan, Y.K. Kim, Y.-M. Kong, I.S.

Park, T.S. Bae and M.H. Lee: Thin Solid Films 562 (2014) 561­567.140) R.C. Zeng, W.C. Qi, Y.W. Song, Q.K. He, H.Z. Cui and E.H. Han:

Front. Mater. Sci. 8 (2014) 343­353.141) J. Rodriguez-Duarte, R. Dapueto, G. Galliussi, L. Turell, A. Kamaid,

N.K.H. Khoo, F.J. Schopfer, B.A. Freeman, C. Escande, C. Batthyány,G. Ferrer-Sueta and G.V. López: Sci. Rep. 8 (2018) 12784.

142) L. Cui, L. Sun, R. Zeng, Y. Zheng and S. Li: Sci. China Mater. 61(2018) 607­618.

143) Y.K. Kim, K.B. Lee, S.Y. Kim, Y.S. Jang, J.H. Kim and M.H. Lee:Sci. Rep. 8 (2018) 13264.

144) M. Echeverry-Rendon, V. Duque, D. Quintero, S.M. Robledo, M.C.Harmsen and F. Echeverria: J. Biomater. Appl. 33 (2018) 725­740.

145) Y.-K. Kim, Y.-S. Jang, S.-Y. Kim and M.-H. Lee: Appl. Surf. Sci. 473(2019) 31­39.

146) K. Edalati, Y. Ikoma and Z. Horita (eds.): Proc. GSAM2018, IRC-GSAM, (Kyushu Univ., Fukuoka, Japan).

R.Z. Valiev, E.V. Parfenov and L.V. Parfenova1366