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Advanced multifunctional zirconia ceramics for long-lasting implants

Final Report Summary - LONGLIFE (Advanced multifunctional zirconia ceramics for long-lasting implants)

Executive Summary:
LONGLIFE project aimed at:
- Developing new zirconia-based ultrafine poly-phasic composites able to answer the specifications in terms of mechanical properties, stability with time, biocompatibility,
- Developing new surfaces by both topography and chemical modifications and assessment of their superiority in terms of biological response,
- Designing ceramic dental implants and intervertebral mobile prostheses able to resist mechanical demands, by a computer-assisted approach. Our goal was to avoid strategies often developed when ceramic implants designs are simply copied from metals with minor adjustments,
- Designing and implementing new testing methods able to mimic the complexity of in-vivo mechanical solicitations or biological environment.

In the framework of new materials development, a new nano-powder engineering route able to produce complex multi-phasic powders was developed and patented. The approach has been exploited to process bulk composite materials after sintering, which exhibit a complexity and grain-refinement never reached before. In particular, Ceria-stabilized zirconia powders have been doped so as to obtain tri-phasic zirconia-alumina-aluminates composites able to meet the demand for high strength (> 1 GPa), high toughness (> 10 MPa√m), perfect stability (no aging during the lifetime of the implant) and wear resistance (sufficient hardness). Selected compositions were up-scaled. A precise study of composition / sintering temperature / microstructure / properties relations allowed to obtain industrial composites with the desired stability and mechanical performances to process prototypes and forecast industrialization of dental implants.

In the framework of new surface development, several strategies were developed and assessed to increase biological functions without compromising the mechanical performances of implants. Combination of materials selection (see above) / mechanical and chemical treatments allowed us to obtain targeted roughness with a minor decrease in mechanical strength, which was not obtained so far for example with current 3Y-TZP implants. At the same time, physico-chemical modifications were also successfully developed to improve the wear behaviour of zirconia mobile spine implants or to provide antibacterial character to dental implants. New materials and surfaces were assessed in terms of biological response by non-conventional approaches. We aimed at considering the complexity of the biological environment during in vitro testing, by using co-cultures or the complex composition of saliva in the oral cavity. The LONGLIFE composites associated to specific surface features (porous coatings or sandblasted surfaces) exhibited very promising features, as they induced very promising bone integration and low risk of infection. More precisely, compared to Titanium or 3Y-TZP, the new composites-surfaces combination exhibited the lowest degree of bacterial adhesion and the highest degree of bone apposition.

Finite Element Analysis of both dental and spine implants under the complex loading observed in vivo was conducted, with the aim of decreasing the risk of failure to the lowest extent. Several analysis loops were conducted and compared to experimental results in order to iterate to the optimal geometrical shapes. Dental implants and intervertebral spine prostheses were developed with optimal features, in terms of balance between mechanical primary fixation and mechanical integrity. The design has been translated to the production of prototypes for testing. The consortium has also considered modelling of a complete spine with or without an implant, in order to understand the effect of prosthesis on the adjacent levels and to demonstrate the benefit of a mobile prosthesis versus the benchmark fusion devices. It has been shown that mobile spine joints restore the highest degree of mobility without stressing the adjacent levels, which proves that the option taken by LONGLIFE is very promising.

Implants have been tested under advanced multi-physic approaches combining wear, shocks and aging in the case of mobile spine implants and fatigue and aging in the case of dental implants.

Project Context and Objectives:
The aim of LONGLIFE was to develop new multi-functional zirconia-based composites for oral and spine (lumbar inter-vertebral disc) implants, with the aim of a perfect reliability and a lifetime longer than the life span of patients. In other words, the aim was to process ‘implants for life’. Such an ambitious goal, motivated by the risks and costs associated to revision surgery, could only be reachable by an improvement of the Low Temperature Degradation (LTD) resistance of zirconia and by an enhancement of the osseointegration capabilities of ceramic implants in contact with bone. As zirconia-based ceramics are the only oxides able to couple high stress resistance and fracture toughness thanks to transformation toughening, a strong effort must be given to the improvement of their stability in the presence of water, without decreasing their toughness and strength. This can be done through the development of new zirconia systems alternative to the common yttria stabilized zirconia, which has shown its limits in terms of resistance to LTD. Osseointegration can be improved by the chemical and topographical modification of the surface. The consortium aimed at producing implant surfaces able to decrease the risk of bacterial adhesion and improve bone apposition, for better clinical success. Given the specific nature of ceramics, especially versus the risk of brittle failure, LONGLIFE aimed at developing new ceramic-oriented designs for the implants, and not just ‘copy and paste’ from metal implants as it is generally done at present. This ‘implants by design’ approach will ensure a better, long-lasting success of oral and spine implants. At last, the LONGLIFE consortium aimed to develop accelerated tests able to reproduce more effectively the different degradation mechanisms and their interplay in a multi-physics approach, in order to ensure an implant reliability and lifetime superior to current implants.

In short, the aim of LONGLIFE was to:
1. (WP1) Develop new zirconia-based materials exhibiting high resistance to wear, fatigue, shocks and perfect stability in vivo. This was particularly important for spine implants for which no failure is acceptable.
2. (WP2) Develop new surfaces, able to decrease the risk of bacterial adhesion and improve osseointegration, while maintaining a high level of mechanical resistance.
3. (WP3) Develop new ceramic implant designs by numerical approaches, further validated by experiments, integrating the key features of ceramic materials and in vivo solicitations.
4. (WP4 and WP5) Transfer the materials/surfaces/designs development into real products and prepare industrialization.
5. (WP6) Develop relevant in vitro tests able to reproduce more effectively the different degradation mechanisms and their interplays in a multi-physic approach, in order to better estimate implants lifetime.

The overall strategy of LONGLIFE is described in the introductive schematic figure in attachment.

Specific objectives of the project are detailed below for each technical Work Package.

WP1: New Materials development

This WP aimed at improving reliability and stability of ceramics implant by developing new tough, strong and stable zirconia based materials. A nano-powder engineering approach able to translate the concepts of increasing the fracture toughness by implementing particulate and platelet reinforcement in ceria stabilised zirconia was to be developed and scaled up.

The main tasks were to develop tailored nano/micro structures aimed to increase at the same time strength and toughness and to suppress LTD. This was planned by several complementary approaches:
- Post doping commercial Ce-TZP powders (Ce-TZP being non sensitive to LTD, contrarily to Y-TZP) and to develop bi-phasic and tri-phasic composites (refining the grain size and adding an additional reinforcement with platelets being the two main objectives to improve strength-toughness relations),
- Investigating alternative dopants to Yttria or Ceria or co-dopants,
- Optimizing the nano-composite powder compounding and sintering to orient the nano/micro structures development to the targeted features.

Finally the whole process is to be scaled up, including powder production, shaping and sintering from the laboratory scale to industrial scale for the production of the parts necessary in WP4 and WP5.

WP2: New Surfaces & biological assessment

The objectives of WP2 were to develop optimized surfaces for zirconia-based implants and to assess their biological properties. Its specific objectives were to:
- Evaluate the biocompatibility of the newly developed zirconia-based materials,
- Improve hard and soft tissue integration of the implants,
- Reduce the risk of infection at the implant site by antimicrobial properties,
- To keep or improve the mechanical performances and the stability of zirconia versus LTD after surface modifications.
The biocompatibility and biological interactions were assessed by a series of complementary techniques, such as gene profiling, cell culture evaluation, by bioreactor evaluation and also by an animal study. Interactions with microorganisms were assessed via antimicrobial surface testing, initial bacterial adhesion and biofilm formation.
In addition to a comprehensive characterization of the new materials and surfaces developed in LONGLIFE, our aim was also to develop new testing protocols, such as bioreactor evaluation directly on implants or co-cultures of different cell lines at the same time. Such improved testing methods, closer to the body situation, were developed in order to answer the need of more relevant biological testing methods before (or even as alternative) to in vivo trials.

WP3: Computer assisted design modeling

The objective of WP3 was to define the best dental and spine implant designs with the use of numerical simulations, taking into account the complex mechanical loading of implants in vivo and the specificity of ceramics versus failure. We conducted this approach by Computer Assisted Design (CAD) and Finite Element Analysis (FEA), with the aim of reducing the number of design testing loops and experimental tests.

WP3 specific objectives were to:
- Determine the mechanical loads applied on the implant and surrounding bones from the analysis of the human body movement.
- Realize the loops designs and define the most accurate simulations of the implants design.
- Analyse the gap between simulation results and accelerated laboratory tests (WP6), in order to improve the simulation hypotheses and iterate towards improved geometries.
- Develop new ceramic implant design,s which are not just a copy-paste from metal devices, with the highest degree of mechanical performances.

WP4: Implants design and prototyping

WP4 aimed to design and to develop the process of new multifunctional implants with improved properties as compared to existing solutions. Its specific objective was to:
• Design ceramic implant reducing the risk of failure in vivo to zero;
• Develop multi-functional implants with improved surface properties, favouring short term and long term integration of bone and limit the risk of infection;
• Develop industrial process to produce such implants;
• Produce dental and spinal implant prototypes for testing;
• Design ceramic implants with minimum environmental impact.

WP5: Towards industrialisation

Oral implants offer an effective treatment for partial and total edentulism. It is reported that the oral implant number will grow at a rate of 6% per year from 2010 to 2015, since there is a tendency to propose more and more implants to patients to improve their quality of life (aesthetic, but also mastication and long-term stability). Oral implants made of metal sometimes suffer lack of osseointegration and/or must be replaced because of bacterial infection. Some scientific publications have shown sensitization to titanium or allergic reactions. Furthermore, patients ask for completely metal-free dental reconstructions. Therefore, zirconia ceramics are entering the market as implant materials, but their use is limited, because of issues concerning their mechanical properties and their stability in vivo. Especially, dental zirconia must be improved by an extent that has never been reached so far in terms of a compromise between toughness-strength and stability in vivo. Zirconia-based composites are the only oxide technical ceramics able to be used as structural bio-ceramics able to withstand very high loads for long durations.

A major goal of spine surgery is to remove the disabling pain caused by abnormal movements of the vertebrae (pinched nerve, joint pain). Historically, movement disorders are treated by fixation and bone fusion using products such as pedicle screw system, and intervertebral cage systems by posterior or posterior-lateral surgical approach. Patient's pain is therefore cancelled but with a loss of mobility. This introduces also additional loads on the other disks, leading to their accelerated degradation. There is therefore a high attractiveness for a lumbar disc prosthesis that restores some mobility. However, there is so far no attempt to introduce devices with ceramic-ceramic friction in the lumbar region, such as it is the case for hip joints. If one refers to the experience of hip prostheses, no lumbar disc implant currently on the market is responding adequately to the problem of wear of the lumbar disc prosthesis, because metal-polyethylene and metal-metal coupling have both shown their limits.

LONGLIFE’s goal was therefore to develop new zirconia based implants with a high degree of reliability and stability in vivo, based on new the materials developed in WP1, new surfaces developed in WP2 and new designs developed in WP3 and WP4.

In practical terms, WP5 aimed to define and validate processes able to produce implants in large series ready to be marketed and prepare certifications for future industrialization. Its specific objectives are to:
• Validate a safe and consistent process for the production of large series,
• Obtain all certifications
• Prepare market and clinical strategies
• Prepare Environmental Product Declaration of ceramic implants

WP6: Test set-up and long term assessment

Introducing new implants on the market necessitates a proof that they are at least as reliable as existing ones. During their lifetime, medical implants are submitted to numerous solicitations from mechanical, thermal, biological and chemical origins. Thus assessing their reliability involves testing different aspects of their behaviour, preferably at the same time so that mutually-accelerating degradation processes can be evidenced.
Thus WP6 aims to ensure that the implants developed during the project are safer, more reliable and more efficient than existing implants, both for spine application and dental application and that they will exhibit the expected lifetime.
Its specific objectives are to:
• Establish new protocols for ceramic implant lifetime assessment.
• Use these new protocols to assess the reliability of the implants developed in LONGLIFE,
• Ensure 60-years lifetime of the implants;
To reach these objectives, and in the framework of this project, UKL-FR developed a chewing simulator able to simulate also the hydrothermal degradation of implant materials, through increased temperature of the liquid medium; INSA developed a test sequence for spine implants involving fatigue, decoaptation on a specially developed spine simulator, hydrothermal ageing in autoclave and wear.

Project Results:
LONGLIFE project has been very successful and meets the majority of challenging goals defined when the proposal was submitted, thanks to an involvement of all partners, all going in the same direction. There were few deviations, as usual in ambitious projects, but the main derivations were due to external contexts (e.g. change of the EU rules concerning spine implants) or an underestimation of task force to answer a need (number of samples to provide for biological testing) rather than because a partner failed to do so.
The projects has been successful in terms of science, with the development of a new class of tough, strong and stable zirconia-based composites and new surfaces able to increase osseo-integration and decrease bacterial adhesion. It has been fruitful in developing a specific strategy of engineering ceramics, i.e. developing specific ceramic implants considering their brittle nature.
The project has also been successful in developing Intellectual Properties and for future exploitation, mainly with the patent filed on nano-powder engineering, but also with surface modification techniques that could be further exploited or new products that will be launched in the dental field and by extension in structural demanding applications.
The project has been successful in developing improved in vitro testing methods able to consider the complexity of degradation mechanisms or the biological environment. Such improved protocol could serve as a basis for further ISO standard.
Last, it has been successful in creating a strong network at the European level on biomedical ceramics.

Main results are highlighted below specifically for each Work package.

WP1: New Materials development

Highlighted results:
- A new post-doping route to synthetize complex inorganic powders and its implementation to process multi-phasic composites with a fine tuning of their composition and their microstructure (patented),
- Ce-TZP based composites with excellent mechanical properties and insensitive to Low Temperature Degradation, meeting the initial goals of LONGLIFE (published in Biomaterials),
- Scale-up successful for the production of implants.

Task 1.1 Nano powder engineering
A systematic study on tetravalent dopants of zirconia as well as combinations of tri- and pentavalent dopants has been conducted. Doping with tetravalent elements or a combination of tri- and pentavalent dopants indeed insures a perfect safety versus LTD, which is the main drawback of Y-TZP. For this reason a wide bibliographic research was carried out by POLITO. A deepening on this topic was carried out by INSA, thus to definitely select the new stabilizers for zirconia. Several alternatives were proposed and tested, as described after, but the consortium (in agreement also with the Scientific Advisory Board of the project) decided to keep the most promising and safe option (even if not the newest) by using Ceria as a dopant.
Following the preliminary selection of Ceria as a dopant, a process to produce Ce-TZP based composite materials was set-up. The process involves the development of two kinds of secondary/ternary phases: on one side, -alumina with rounded-like morphology was selected; on the other, aluminates with elongated morphology were chosen. α-alumina grains evenly distributed in the zirconia matrix were selected with the aim of limiting zirconia grain growth during sintering, while elongated aluminates were chosen to benefit from an additional reinforcement mechanism (crack deviation) to t-m transformation toughening. If the strategy of developing tri-phasic systems was not fully new, the concept of post-doping zirconia powders to obtain a tri-phasic composite was never explored so far for tri-phasic inorganic systems. A scheme of the process is shown in Figure 1 consisting on few basic processing steps: once obtained a well dispersed zirconia suspension, it is mixed with an aqueous solution containing the inorganic precursors (metallic salts) of the desired second phases and then spray dried. A low-temperature treatment was carried out on the as-spray dried powders, in order to induce the by-products decomposition. The expected second phase was finally produced under controlled thermal treatment carried out in the range 900°C-1150°C.

Task 1.2 From Powders to materials
A HRTEM analysis (carried out at INSA-Lyon), equipped with an EXD nanoprobe, able to determine the chemical composition of the single constituent phases in the composites was carried out to confirm that the chosen composite performs as predicted. A TEM micrograph of a sintered ZA8Sr8 composite (i.e. Ceria doped zirconia as the matrix, 8 vol.% alumina, 8 vol.% of Strontium Aluminate) is illustrated in Figure 2 (b), showing a very good match between the developed and the three-phase microstructure targeted at the beginning of the project (compare Figure 2 a and b). The observation allowed recognizing brighter regular-shape, darker elongated- and equiaxial-shape grains. To define the chemical composition of the particles having different morphologies and phase contrast, EDX nanoprobe was focused on the grains referred to as A, B and C in Figure 2 (b). The corresponding atomic compositions are shown in the Figure 2 (c): even if a low zirconium amount was observed both in A and B grains due to a matrix effect, a quite perfect agreement with their nominal compositions was found. In fact, in the point A (dark elongated grain), an atomic Sr:Al ratio of 6:87 (=1:14.5) corroborates, within the instrumental error (thin foil geometry could influence uncontrolled absorption effect), an aluminate phase composition very close to SrAl12O19. At the same time, it was confirmed that the dark equiaxial grain (grain B) was pure alumina. Regarding the brighter grain (point C), it is pure zirconia stabilized with ceria: the atomic Zr:Ce ratio of 90:10 showed a zirconia stabilization degree lower than the expected value (Zr:Ce ratio of 90:11) but still within the instrumental error. Since cerium was detected only inside the zirconia grains, TEM analyses confirm its complete diffusion inside the zirconia lattice during thermal treatments, thus corroborating the ability of the applied method in fine-tuning the zirconia stabilization degree. Such a fine-tuning of the composition of the zirconia phase and of the microstructure at the nanometric level would not be possible by more standard methods such as powder mixing. The post-doping method appears therefore as the method of choice to develop multi-phasic systems with a fine-tuning of the composition of each phase and with an exceptionally fine microstructure. The process of post-doping an oxide by two or more additional phases and applied to zirconia based materials has been patented by the three partners DMC, POLITO and INSA.

Also alternative dopants were investigated. By a bibliographic research, a very promising system was the +3/+5 one, in which equi-molar and large amounts of Nb2O5 (or Ta2O5) and Y2O3 are added to zirconia. These conditions allow, in fact, the retention of the tetragonal zirconia phase at room temperature, without producing oxygen vacancies that make the material susceptible to LTD.
As a second option, the system +3/+4, in which co-stabilization is provided by Y3+ and Ce4+, seems also promising. In fact, even though this strategy does not allow the fabrication of totally aging-free materials, the LTD kinetics is reduced to such an extent to assure no degradation for many years.
These two systems were developed by PCT through a plasmochemical synthesis technique, and a preliminary powder characterization was carried out at POLITO. In the case of yttria/niobia co-doped zirconia powders, some critical issues were pointed out, since no single-phase zirconia solid solution was yielded, and powders showed a very poor sinterability. On the opposite, promising results were obtained in the case of yttria/ceria co-stabilized zirconia system, since fully dense and fine sintered materials, made of pure tetragonal zirconia phase, were successfully produced.
As written above, mainly because of a constrained time-scale in the project and the need to develop rapidly robust solution for further prototyping, these alternatives will remain promising at the lab. Scale, since they were not scaled-up.

Task 1.3 Processing scale up and technological transfer to industrial partners
One of the most challenging issues (and one of the most critical) for the project was the scale-up of powder synthesis and compounding. PCT (assisted by POLITO) was in charge of developing nano-powder engineering at a larger scale for industrial production. However, as the technology (Plasma technology) used by PCT to synthetize ceramic powders was different from the post-doping route developed at POLITO, and also because of large-scale productivity issues, it was agreed to assess alternative strategies. Namely, it was agreed, during M12 management meeting in DMC to develop two parallel paths:
1: scale-up of zirconia based composite powders by Plasma Technologies (PCT, with the support of POLITO)

2: scale-up of zirconia based composite powders by Daiichi, after signature of NDA. This alternative solution was motivated by the fact that Daiichi is the main producer of Ce-TZP powders worldwide and that DCM already had strong contacts with this company. As for solution (1), it was recognized that the synthesis methodology was somewhat different from the post-doping route developed by POLITO, thus would lead potentially to different microstructures and that the difference has to be assessed.

Therefore the differences between materials processed from the powders synthetized by POLITO and DAICHI were investigated.
The results showed that the morphology has the same features, Ceria-stabilized Zirconia grain, Alumina grains and elongated Strontium Aluminate Structures, but the size of these crystallites differs markedly (Figure 3 shows the same system sintered at the same temperature, but with the DAICHI or POLITO powder).

Therefore the Ceria content and the sintering temperature of the up-scaled composite was adapted to match the desired features found in the POLITO compound. Refinement to the degree obtained at the lab. Scale by POLITO was not possible but tuning of the Ceria content and sintering temperature led to equivalent mechanical strength and toughness. This shows however that the post-doping procedure was the most likely to obtain very fine microstructures.
Given these limits, upscaling was quite successful with the powder synthetized by DAICHI and mechanical properties were quite similar to the materials processed with the POLITO powders.
The up-scaled compound showed a pseudoplastic behaviour that results in a very high Weibull modulus of up to 60. Figure 4 shows the behaviour in a biaxial bending test of a composite with a too high Ceria content. For this composite, the strength remains limited. On the other side, a high degree of plastic deformation (associated to t-m transformation) was observed, together with a very high Weibull modulus. However, strength was considered as too modest for this composition, and the material suffered stability during cooling (see below). A composition with 11.5 Mol.% of Ceria in the composite was preferred, with a higher strength (higher stress to transformation, leding at the end to a strength of 1100 MPa as measured in biaxial bending) and a much better stability.

The microstructures and properties of the LONGLIFE compositions (ZA8Sr8-CeX where X=10.5 or 11 or 11.5) processed under industrial scale, i.e. with the powder synthetized by DAICHI and with all steps of the process done by DMC (and ANTHOGYR for dental implants) were carefully assessed at the end of the project. As expected, mainly because the powder was not synthetized in exactly similar conditions than by POLITO, the microstructures of the composites processed at the industrial scale did not reach the degree of refinement of the composites processed with the post-doping strategy. This led even to unexpected ‘explosion’ of the bars during cooling in the sintering furnaces, associated to a tetragonal – monoclinic transformation. A careful examination of this process and monitoring of the t-m transformation versus composition and sintering temperature allowed fortunately to correct this issue and provide compositions ((ZA8Sr8-Ce11.5 sintered at 1450°C) stable enough for further production of samples and prototypes. This issue led us however to emphasize again on the strong variability of zirconia based materials to process and to define clear specifications and control for further industrial development of the composite.

This powder (ZA8Sr8-Ce11.5) which has to be sintered at 1450°C, is now available in industrial amounts and the material was used to make implants for the WP 4 and 5.

Task 1.4 Characterisation
The achievement of UTRIESTE within this WP1 is constituted by the establishment of the protocol to be used by the whole consortium for the determination of the aging of all zirconia samples.
The t-m determination on zirconia samples is based on the different Raman spectra of the two polymorphs, as can be seen in the following picture Figure 5. In this picture it can be clearly seen that there a doublet, at 180-190 cm-1 increasing in intensity with decreasing temperature: this doublet belongs to the monoclinic polymorph and, from the relative intensities of the peaks at 145, 180 and 190 cm-1, it is possible to determine the monoclinic content of the zirconia samples under investigation.

Coupling Raman spectroscopy with statistical methods based on Principal Component Analysis, we have found out that single Raman spectra would indicate, at a normal inspection, no presence of monoclinic, whereas a PCA analysis on larger ensembles of spectra leads to the determination of the presence of monoclinic contents below 1% vol. An example is reported in Figure 6.

WP2: New Surfaces & biological assessment

Highlighted results:

- Chemical and mechanical modification of surfaces successful: different strategies were explored to modify the wear properties of bearing surfaces or to modify the Osseo integrative or antibacterial properties of surfaces in contact with bone (publication in Materials)
- LONGLIFE composites could be modified by Sandblasting without drop in strength, while 3Y-TZP benchmark was highly affected. This demonstrates the superior flaw resistance of LONGLIFE composites and allows to reach sufficient level of roughness without compromising laod to failure of implants,
- LONGLIFE composite in the form of a porous coating favours bone apposition in vivo and shows superior biological properties than Benchmarck 3Y-TZP and Titanium, with lower bacterial adhesion (publication in Materials).
- Improved biological testing methods, closer to the body situation, were developed in order to answer the need of more relevant biological testing methods before (or even as alternative) to in vivo trials.

Task 2.1 Development of new surface morphologies
Based on the experience of implant producers (KISCO and ANTHOGYR) and clinicians (UKL-FR), work package members decided to prepare surfaces with a mean roughness (Ra) from 0.02 µm to 1.5 µm and different surface topographies from dense to microporous. Smooth surfaces are required to reduce wear between the components of mobile spine prostheses and to reduce microbial adhesion on the transgingival part of dental implants. Rougher and microporous surfaces enhance osteointegration of implants. The necessary methods to obtain these surface characteristics on zirconia implants have been developed by DMC and SWEREA.
DMC has performed grinding in the un-sintered state to modify Y-TZP surfaces. This leads to surfaces with a high roughness that can be tuned over a wide range by the choice of the grit size. The highest roughness values obtained this way are of special interest to obtain an initial mechanical fixation of spinal implants. Machining is used to obtain reference surfaces of defined roughness values. Furthermore it is shown by SWEREA that machining can also be used to prepare complex surface structures that will allow for mechanical fixation of implants in the bone. Blasting is used to increase the surface roughness of parts either in the pre-sintered or in the sintered state. By choosing the appropriate blasting particle size, SWEREA obtained the full range of desired roughness values.

Task 2.2 Development of new surfaces by chemical modification
Using a colloidal coating procedure, ceramic material can be applied on either pre-sintered or sintered substrates. SWEREA successfully obtained very thin calcium phosphate (CaP) layers on zirconia. Those should increase osteointegration without the risk of coating delamination associated to common, thicker coatings.
NTTF developed zirconia coatings and nitrogen-doped amorphous carbon coatings. The coatings can be stored in the hydrophilic state for prolonged periods of time. Due to the increased hydrophilicity, the coatings should improve tissue integration and decrease bacterial adhesion. Furthermore, the adhesion of amorphous carbon coatings to zirconia was improved by new processes involving combined magnetron sputtering with plasma-enhanced chemical vapour deposition as well as high power impulse magnetron sputtering. This way, suitable coatings for wear reduction in articulating zirconia implants were obtained.
Since there was initially not enough LONGLIFE composite material to prepare samples for biological investigations, SWEREA developed a colloidal spray coating technique to deposit a thin layer of composite material on conventional 3Y-TZP samples. To compare 3Y-TZP to the composite ZA8Sr8-Ce11 while retaining the same topography, a coating of both materials was applied by the same procedure on pre-sintered substrates of 3Y-TZP. When sintering the pre-sintered substrate and the coating, the homogeneous shrinkage densified both the substrate and coating. To obtain a different surface topography, the composite material was applied on sintered substrates. Furthermore the ceramic suspension contained an addition of polyethylene glycol in order to reduce the packing density of the particles in the coating. When the coating was densified, shrinkage was only allowed in one direction due to the already dense substrate, which in combination with a reduced particle packing in the coating contributed to an increased porosity of the coating.

Task 2.3 Mechanical properties and long-term stability of modified surfaces
Contrary to 3Y-TZP, the bending strength of the tougher LONGLIFE materials is only slightly reduced by blasting with alumina particles to a surface roughness of 1.5 µm. Therefore blasting of the LONGLIFE material to the desired roughness is possible without compromising mechanical properties.
SWEREA showed that both the composition and microstructure are important for the material strength. The influence of the composition can be illustrated by the increase in strength, when the ceria content was increased from 10.5 mol. % or 11.0 mol.% to 11.5 mol.% in the LONGLIFE composites sintered at 1550 °C. When the sintering temperature of the LONGLIFE composite with 11.5 mol.% ceria was reduced to 1450 °C, the grain size was reduced. This allowed the strength to be further increased to about 1100 MPa, while the material still was rather insensitive to the blasting procedure.
UTRIESTE analysed the monoclinic content in and around laser-marked regions on zirconia samples by Raman spectroscopy with principal components analysis (PCA). Monoclinic zirconia can only be detected in small amounts in a few spots of the laser-marked surface. This way it has been demonstrated that laser marking does not provoke the unwanted tetragonal to monoclinic transformation, and laser marking is a viable way to identify zirconia parts. Furthermore Raman spectroscopy showed that samples made of 3Y-TZP can be etched to the desired surface roughness without inducing crystal phase transformation from tetragonal to monoclinic. Wear tests performed on 3Y-TZP and the composite material ZA8Sr8-Ce11.5 did not induce any phase transformation either. Therefore neither surface treatment by etching nor wear during the lifetime of the implants is a risk factor for accelerated ageing.
NTTF showed in tribological ball-on-disc experiments that wear and friction of zirconia could be reduced significantly by amorphous carbon coatings. In the experiments performed in diluted bovine serum at 30 °C the coated zirconia parts performed as well as alumina parts opening the route for the application of coated zirconia in high-wear settings like spinal implants.

Task 2.4 Biological effects & biocompatibility assessment
Subtask 2.4.1: Gene Profiling
In order to evaluate the initial response of implant-relevant target cells, namely primary human alveolar osteoblasts and gingiva fibroblasts, to novel Ce-TZP-based implant materials with different surface topographies, we analysed the expression pattern of genes mediating cell adhesion, cell proliferation and differentiation, as well as inflammation. Therefore, UKL-FR and SWEREA first performed surface characterization of the zirconia-based materials by scanning electron microscopy (SEM) and interferometry (IFM) to describe the surface topography. The materials/surfaces used for cell culture consisted of Y-TZP disks coated with Y-TZP (O1 and F1, control groups), LONGLIFE composite (O2, S1 and F2), and LONGLIFE composite with overlaying hydrophilic pure zirconia coating (O4) deposited by direct current magnetron sputtering. The surfaces O1, O2, S1 and O4 were used for osteoblast culture, while F1 and F2 were used for fibroblast culture. For gene expression analysis, UKL-FR used the human pathway-specific RT² Profiler™ PCR Array which profiles the expression pattern of 84 genes.
Regarding surface topography, IFM and SEM analysis revealed similar surface properties for O1, O2 and O4, while the porous composite coating of the S1 group had the lowest average height deviation amplitude (Sa), the highest number of peaks per area unit (Sds), and highest surface enlargement (Sdr). By contrast, F1 and F2 displayed similar surface characteristics and were generally smoother than surfaces of the osteoblast group.
The relative gene expression of 84 genes was determined on the mRNA transcription level by quantitative RT-PCR after 24-hour and 7day culture periods. Relative gene expression of biomarkers under study on O2, S1, O4 and F2 surfaces was then compared with matched controls, namely O1 and F1. The cell culture experiments were performed in triplicates in three independent experiments. Our results revealed comparable gene expression patterns in osteoblasts on both LONGLIFE surfaces (O2 and S1) when compared with the Y-TZP control group (O1). By contrast, on ZrO2 (O4) genes encoding for pro-inflammatory cytokines, known to inhibit osteogenesis, were significantly up-regulated, while genes encoding for ECM proteins were concomitantly down-regulated. Based on these data we proposed to exclude the O4 surface from further cell culture testing. Regarding fibroblast-specific surfaces, it was striking that on day 1 distinctly more genes were differently - albeit not significant - expressed between F1 and F2 than at day 7, indicating that initial fibroblast response was modulated by the type of biomaterial.
By means of global gene expression analysis in periodontal tissue cells on ceramic-based biomaterials, we were able to identify pro- and contra-supportive implant surfaces for osteogenesis. Moreover, our results indicate that initial cell response of osteoblasts and fibroblasts was modulated by the type of zirconia in a time-dependent manner. The results of the present work further highlight the importance of cell culture-based preclinical screening analysis in the course of implant biomaterial development and evaluation.

Subtask 2.4.2: Cell culture evaluation
WP2 aims to develop optimized surfaces for zirconia-based implants and to assess their biological properties. Its specific objectives are to evaluate the biocompatibility of the zirconia-based materials, to improve hard and soft tissue integration of the implants, to reduce the risk of infection at the implant site by antimicrobial properties, and to keep or improve the stability of zirconia.
On the basis of the data resulting from subtask 2.4.1 the best 3 materials/surfaces were selected for further in vitro characterization in cell cultures.
In order to examine osteoblast and fibroblast response to the new ceria-based LONGLIFE composites (O1, O2 and S1 for osteoblasts, and F2 for fibroblasts) and control groups (O1 and titanium for osteoblasts, and F1 for fibroblasts) we analysed initial cell attachment and morphogenesis by scanning electron microscopy (SEM) and quantitative morphometry of fluorescence-labelled cells. Cell proliferation and metabolic activity were determined by DNA quantification and alamarBlue™ metabolic assay, and long-term attachment, as well as ECM deposition and mineralization were examined by histological staining with Azur II, Alizarin Red S (ARS) and Sirius Red / Fast Green. In addition to standard monocultures for cell culture evaluation, we used a more physiological interactive coculture model comprising osteoblasts and fibroblasts for the first time.
The results from the present work revealed comparable osteoblast and fibroblast functions on all examined LONGLIFE composite surfaces under study with matched Y-TZP and titanium controls. Our data further showed that long-term attachment of newly formed mineralized ECM by osteoblasts was best on porous S1 composite and microstructured titanium surfaces, while ECM attachment to conventional Y-TZP (O1), exhibiting a less textured surface, was worst or even completely missing. Moreover, by using a new coculture model comprising HGF and HABO we were also able to show that HGF synthesized irrespective of the biomaterial type a more physiological ECM with higher collagen amount and significant ECM contraction, similar for normal wound healing, when compared to monocultures.
Based on our data it can be concluded that the new LONGLIFE composite demonstrated good biocompatibility and that the porous Ce-COMP surface was even superior to conventional Y-TZP in terms of long-term attachment of mineralized hard tissue-specific ECM. In addition, we showed that the novel coculture model represents a promising tool as an in vivo-like test platform for biocompatibility assessment.

Subtask 2.4.3: Bioreactor culture
Due to the late delivery of the implant test specimens for the bioreactor, no results can be presented. The investigations are underway, but will be finalized after the termination of the project.

Subtask 2.4.4: Animal investigation
Miniature implants made of Y-TZP and coated with either a colloidal suspension of Y-TZP (group O1), or zirconia-based composite ceramics (ZA8Sr8-Ce11 = 84 vol% ZrO2 - 8 vol% Al2O3 - 8 vol% SrAl12O19 – 11 mol% ceria in ZrO2) (groups O2 and S1) and control titanium (Ti) implants were placed into the femurs of 64 Sprague-Dawley rats. To compare 3Y-TZP (O1) to the LONGLIFE composite material ZA8Sr8Ce-11 (O2) while retaining the same topography, a coating of both materials was applied by the same procedure on pre-sintered substrates of 3Y-TZP. The coatings were applied by spraying of a colloidal suspension of the ceramic powders that were prepared by ball milling with 1 % of dispersant. When sintering the pre-sintered substrate and the coating, the homogeneous shrinkage allowed both the substrate and coating to be densified (O1). The thickness of the dense coating was a few microns. For group S1, the Ce-TZP-based LONGLIFE composite material was applied on sintered substrates of 3Y-TZP. The suspension used contained also an addition of polyethylene glycol in order to reduce the packing density of the particles in the coating. When the coating was densified, shrinkage was only allowed in one direction due to the already dense substrate, which in combination with a reduced particle packing in the unsintered coating contributed to a surface structure with an increased texture of the sintered implant.
Implant surface topography was analyzed by white light interferometry and scanning electron microscopy (SEM). After healing periods of 14 and 28 days, respectively, histologic evaluation and biomechanical testing was performed. The animals were killed after the respective time points and the femurs were dissected free. For histological analysis, the femurs were processed according to the cutting-grinding technique. For the biomechanical tests, the femurs were embedded into special metal containers.
The evaluation of the implant surfaces under the SEM showed that the titanium surface could be clearly distinguished from the three zirconia implant surfaces. White interferometry measurements indicated a mean surface roughness (Sa) for the O1 of 0.32 µm and for O2 of 0.34 µm. The Sa values for the S1 surface was 0.77 µm and for the Ti surface 0.81 µm. The Sa values for Ti and S1 were statistically significant different from O1 and O2 (S1 vs O1: p<0.0001 S1 vs O2: p<0.0001 Ti vs O1: p<0.0001 Ti vs O2: p<0.0001). Sa was not different between Ti and S1 (p=0.193) and between O1 and 02 (p=0.318). The Surface Area Ratio or Developed Interfacial Area Ratio (Sdr in %), which is expressed as the percentage of additional surface area through the texture as compared to an ideal plane, amounted to 3.3% for O1, 3% for O2, 43% for S1 and 17.7% for Ti. S1 was significantly different to all other groups. Ti was significantly different from O1 and O2, whereas O1 was not significantly different from O2.
The bone-to-implant contact after 14 days of healing in the cortical bone area was for O1 28.1%, for O2 24.9%, for S1 72.6% and for Ti 10.7%. The respective bone-to-implant contact values in the cortical bone after 28 days of healing were 55.3% for O1, 43.3% for O2, 93.5% for S1 and 16.9% for Ti. The S1 surface showed the highest bone-to-implant contact values after 14 and 28 days. The lowest values were found for the Ti surface. The differences between S1 and O1, O2 and Ti at 14 and at 28 days were statistically significant.
The bone-to-implant contact in the spongious bone areas after 14 days was 29.5% for O1, 20.3% for O2, 46.2% for S1 and 25.1% for Ti. After 28 days of healing the values for the zirconia materials almost doubled whereas the value for Ti remained unchanged (O1: 42%, O2: 47.8%, S1: 81.1%, Ti: 25.4%).
Regarding the push-in tests after a healing period of 14 days values of 10.2 N for the O1 surface, 13.1 N for O2, 23.9 N for Ti and 63 N for S1 were observed. The values of S1 were significantly higher compared to all other groups (all p < 0.0001). No significant differences were observed between the remaining groups. After 28 days of healing, the push-in forces increased in all but the Ti group: O1 = 35.4 N, O2 = 34.5 N, Ti = 9.9 N, S1 = 65.5 N. The differences were still statistically significant between S1 and all other groups (S1 vs O1 p=0.014; S1 vs O2 p=0.009; S1 vs Ti p=0.000). When the timely changes are considered in the groups, the increases of the push-in values for O1 and O2 were statistically significant (p=0.0055 and p=0.0348 respectively). The decrease in the Ti group was also statistically significant (p=0.0360). The change in the S1 group was not significant.
Our findings showed that the zirconia-based composite coating S1 surface rendered the best results regarding osseointegration and the biomechanical stability of the bone-implant interface. Interestingly, the titanium material and its inherent surface used in this investigation performed the poorest. Within the limits of the present investigation, it can be concluded that all ceramic materials seem to be biocompatible and that they might be utilized for the fabrication of oral and spine implants. The surface with the greatest potential seems to be the S1 surface, where the Ce-TZP-based LONGLIFE composite material was applied on sintered substrates of 3Y-TZP.
It is worth a special note that the cell culture evaluation as well as the animal experiment came to the same result that the porous S1 surface performed the best. The new LONGLIFE composite in form of the porous Ce-COMP S1 demonstrated good biocompatibility and was even superior to conventional Y-TZP in terms of long-term attachment of mineralized hard tissue-specific ECM in the cell culture. In the animal investigation, the S1 surface showed the highest implant-to-bone contact as well as the highest force values in Newton for push-in (highest biomechanical strength). The LONGLIFE composite in the form of a porous coating at the surface is the most likely to give very positive results in terms of osseo-integration.

Subtask 2.4.5: Antimicrobial surface testing
Bacterial adhesion to implant biomaterials constitutes a virulence factor leading to biofilm formation, infection and treatment failure. The aim of this study was to examine the initial bacterial adhesion on different implant materials in vitro. Six implant biomaterials were incubated with Enterococcus faecalis, Staphylococcus aureus and Candida albicans for 2 h: 3 mol % yttria-stabilized tetragonal zirconia polycrystal surface (B1a), B1a with zirconium oxide (ZrO2) coating (B2a), B1a with zirconia-based composite coating (B1b), B1a with zirconia-based composite and ZrO2 coatings (B2b), yttria-stabilized tetragonal zirconia polycrystal surfaces (Y-TZP) with nitrogen-containing hydrogenated amorphous carbon (a-C:H:N) coating (B3a) and Y-TZP surfaces with zirconia-based composite (Ce-TZP) and a-C:H:N coatings (B3b). Bovine enamel slabs (BES) served as control. The adherent microorganisms were quantified and visualized using scanning electron microscopy (SEM), DAPI and live/dead staining. The lowest bacterial count of E. faecalis was detected on BES and the highest on B1a. B3a and B3b showed comparable CFUs sheltering greater amounts of E. coli and lower numbers of E. faecalis, S. aureus and P. aeruginosa against BES. Overall, CFUs of C. albicans were similar. The lowest bacterial count of E. faecalis, S. aureus and E. coli and the highest count of C. albicans were detected on BES. The fewest vital C. albicans strains (42.22 %) were detected on B2a surfaces, while most E. faecalis and S. aureus strains (approximately 80 %) were vital overall. On B3b surfaces the fewest vital C. albicans strains (67.9 %) were visualized, while most P. aeruginosa strains (77.2 %) were found vital. B3a and B3b presented similar vitality percentages for E. faecalis and S. aureus against the control. Compared to BES, coated and uncoated zirconia substrata exhibited no anti-adhesive properties. Further improvement of the material surface characteristics is essential.

Subtask 2.4.7: Initial bacterial adhesion and biofilm formation
In the present projected study the initial bacterial adhesion (2 h) and biofilm formation (3 days) on different yttria-stabilized tetragonal zirconia implant surfaces was tested ex vivo. Bovine enamel samples (BES) and titanium (Ti) were used as control surfaces. Additionally, the biofilm formation was determined over a time period of 3 days. The implant material surfaces utilized for the examination of the initial bacterial colonization and biofilm formartion ex vivo were: 3 mol % yttria-stabilized tetragonal zirconia polycrystal surface (B5), zirconia-based composite surface (ZA8Sr8Ce-10.5) with zirconium oxide (ZrO2) coating (B4), zirconia-based composite surface (ZA8Sr8Ce-10.5) (B6), zirconia-based composite surface (ZA8Sr8Ce-10.5) with Ce-composite coating (S1). The adherent microorganisms were quantified and visualized under the confocal laser scanning microscope (CLSM) using DAPI, live/dead staining and fluorescence in situ hybridisation (FISH). No differences were found in the bacterial growth of aerobic and anaerobic cultivable microorganisms between the implant materials and enamel surfaces during the initial adhesion and biofilm formation. The surfaces of B4 and B6 groups presented a higher number of initially adhered live microorganisms compared to the BES, while the surfaces of B5 group exhibited less live bacteria than Ti surfaces. Interestingly, the Ti surfaces presented the higher number of live microorganisms compared to all other surfaces during biofilm formation. The highest percentages of Fusobacterium nucleatum and Streptococcus spp. were detected on BES and Ti surfaces compared to all other tested implant surfaces after three days of incubation. To sum up, compared to BES and Ti, the tested zirconia materials exhibited the smallest amount of live adhered microorganisms and an altered bacterial composition.

WP3: Computer assisted design modeling

Highlighted results:
- FEA allowed to develop ceramic implants with a higher degree of reliability,
- FEA allowed to better develop the testing protocols for implant testing.

After analysing the boundary conditions of the in vivo and in vitro loading (during testing in WP6) the kinematic models of the simulation have been designed to reproduce as realistically as possible the in vivo loading or the in vitro loading occurring during mechanical test developed in WP6.
Those models included features, which were demanding in terms of simulation time (such as contact parameters, coupling of different mechanical behaviour laws, complex greometries…etc…) which needed to be simplified in order to reduce the time of simulation but of course to reproducing the same loading state and stress distribution. This reduced time of simulation allowed us to compute many designs in order to optimize them.
A method to assess the criticality of the designs based on the computation of Weibull modulus (and as a consequence on the probability of failure) has been developed. This was achieved thanks to a statistical tool based on the Weibull distribution parameters (Weibull modulus and Weibull characteristic strength) allowing to measure the criticality of a particular design under specific loading conditions.
For example for the dental implant, the probabilities of failure for different designs have been assessed, cf. Figure 7, thanks to the definition of a Weibull law. Finally this allows to select the most reliable dental implant geometry.

Concerning the lumbar implant, the criticality of the implant was estimated through the first principal stress distribution in the implant during in vivo loading. Then the design has been optimized to reduce the first principal stress and in the meantime, features have been incorporated for the implant osseointegration. Finally thanks to a large number of simulations it has been possible to obtain a reliable design.
Thanks to this model and the method developed we were able to determine the most critical areas of the lumbar and dental implants. Based on parameterized simulation we tested several designs and improved them in order to obtain a probability of failure as low as possible for given loading configurations.
Furthermore dynamical simulation shows that the implant composition has a negligible influence on the compressive stress in the bone of the lumbar vertebrae during dynamic load. Because of the concerns released from the clinicians partners of Kisco about the high stiffness of zirconia based ceramics, a dynamic simulation of a mass falling on the vertebrae fixed on an implant have been performed in order to demonstrate the low influence of the insert materials on the vertebrae stress distribution. The insert thickness was ~1 mm and the loading mass was 100 kg.

The compressive stresses reported in the table above show that the materials stiffness has no influence on the stress distribution in the vertebrae. It should be noted that if the hemisphere insert were made of PEEK, it should absorb a part the potential energy of the mass but this would be negligible in comparison to the absorption from the whole spine.
The main important conclusions that can be drawn from the results:
• The stress state in the implants with the final design depends on the stiffness of the trabecular bone and the presence of a cortical region under the implant. The misfit of Young’s Modulus and stiffness of trabecular / cortical bone rules the final stress at the back of the keel basis. Each patient having a different bone structure, it is evident that each patient after a given surgery (which would also keep more or less cortical bone below the implant) would have a different stress state even for a same applied load. In terms of experimental devices for the assessment of the implants, it is possible to play with the stresses and account for this phenomenon by adding an elastic material between the implant and the fixture developed so far.
• The clearance between the two parts of the prosthesis is a crucial parameter. Large clearances are clearly detrimental. This explains why some prototypes provided for WP6 behave so badly.

The following figure shows that the failure occurs at the position predicted by the simulation, which tends to assess the relevance of the simulations conditions.

Finally due to the difficulties in reproducing the same mechanical loading in vitro as in vivo, further simulations have been carried out in order to optimize the fixture of the mechanical testing and to optimize the pairing of lumbar implants.
In order to do this the last task has been focused on the description of the mechanical behaviour of the new spine implant in the in vitro experimental apparatus.

Simulations of the in vitro experimental fixture used in WP6 have been carried out. Initially the experimental fixture was designed to test the initial implant design. With the modification of the design, this fixture had to be adapted to reproduce the in vivo stress distribution. Lately, a study has been carried out to assess the possible modifications of the apparatus. It has been shown that in order to reproduce the in vivo stress distribution an elastic layer could be inserted between the implant and the support. Also the simulation gave some hints to find the best combination between the top and bottom disc of the implant in order to perform long lasting experiment. In particular, it has been shown that a negative clearance is less critical than a too large one.
During the project a methodology has been developed to simulate the ceramics devices and optimize their design, in particular in case of contact conditions.
Industrial companies exploiting ceramics for their mechanical properties (medical, automotive) in particular SMEs are potential targets to propose this type of simulation.
More generally, our know-how in terms of simulation and the skills that we developed during this project will be exploited for our own products (sensors, 3D printers, feeders, etc…) that we have started to commercialize. The simulation is useful to select the best materials (ceramics, glass-ceramics, metals, plastics, compounds) for their thermal, electrical, mechanical behaviour and to optimize their designs.

WP4: Implants design and prototyping

Highlighted results :
- New dental and spine implants developed from the LONGLIFE materials and with the designs generated from the iterations of FEA and experimental trials were successfully processed,
- The new implants developed are clearly novel versus current state of the art,
- The superiority of mobile prostheses versus fusion devices is demonstrated.

The specifications were defined in task 4.1 to identify the inputs and the needs of the two types of implants.
In task 4.2 a spinal prosthesis and a dental implant were designed and drawings were provided to machine prototypes to validate the first generation of implants and to deliver parts for testing.
In parallel, in task 4.3 different processes were analysed and specified in order to anticipate difficulties to obtain such implants.
DMC, NTTF, SWEREA and ANTHOGYR machined samples, prototypes and implants to support the characterization and the concretization of implant design. Most of these parts were used for testing in WP6.
The Life cycle assessment of prototypes was analyzed in task 4.5 to anticipate and to optimize the manufacturing of implants developed in this project

Task 4.1 Product specification
Dental implant
In the case of dental implants, mechanical performances have been targeted to obtain high-end, reliable solutions without restriction of potential indications, as for usual titanium products. Concurrency and intellectual property reviews were performed to identify existing similar products and to propose innovative solutions. Fulfilling these specifications will allow the LONGLIFE ceramic dental implants to be spread widely over the current niche market of Y-TZP implants.
Spine implant
A global analysis was conducted to obtain an overall view of all specifications needed to develop a medical device to ensure a patient security and a marketable product.
The process of design in KISCO is based on ISO 13485 and the first step in development is to define input data to ensure the patient security and a commercials product.
In this preliminary, bibliography and environmental studies were conducted competitors, standards, IP…):

Task 4.2 Implant design
Design loops were performed during this task due to the feedback of FEA calculation and tests results for dental and for spinal implant.

Dental implant
For dental implants, the safest option, a one-piece implant was drawn as a first prototype, which was simple to serve as a basis for optimization within WP3, to produce prototypes and to provide comparative data with existing systems. This first design already included specific threading in order to fit to ceramic properties. After the first loop of design/simulation/testing, design was then oriented towards optimized one-piece implant in Figure 10. Two-piece implants are in the scope of ANTHOGYR and could be developed in the future.

Spine implant
Some weaknesses were updated and modifications of shapes were performed especially on the sides of the implants in contact with bone to adapt the concept for ceramic design and manufacturing rules. Last drawings including all iterations (including inputs from WP3 and WP6) are visible in Figure 11.

Task 4.3 Process definition
The process definition was made considering different options since the most adapted process could depend on the final material treatment, surface and application.
The most critical steps were identified according to the different options that could be chosen. Some of these critical steps were already validated for current applications (sterilization is an example). Most of the control means are already set up by the industrial partners, which have a quality management system adapted to the production devices.

Task 4.4 Processing of prototypes
Several prototypes of implants were manufactured during this task to characterize shapes and provide parts for all tests. Other parts were manufactured in this task for special tests as wear, bending tests, etc. Spine implant prototypes of different generations provided for testing are shown in Figure 12. They include full-metal implants (useful to develop the multi-physic tests of WP6), metal-ceramic components (first option which rapidly revealed un-sufficient in terms of mechanical resistance), full-zirconia with a first design (which broke at the keel basis during fatigue testing and necessitate a reconsideration of the surface in contact with bone) and last the final design with all improved features.

The different versions of the dental implants are shown in Figure 13, from the starting design clearly detrimental for ceramics towards the final design combined with the LONGLIFE composite and surface modification by sandblasting.

Coating
NTTF has built a medium-scale device to coat implants by magnetron sputtering. The coating device consists mainly of a high vacuum chamber with an appropriate pumping system, mass flow controllers to control the working gas composition and pressure, an infrared heating system for the samples, a specially developed sample holder allowing rotating up to 585 implants simultaneously to obtain a homogeneous coating on the whole implant surface (Figure 14) and two linear magnetrons (11 × 46 cm²) as metal ion sources.

Task 4.5 Life cycle assessment of prototypes
A life cycle assessment was made with respect to the environmental impacts of zirconia dental implants manufacturing process in Figure 15. A functional unit was defined as one dental implant and the material as well as the energy needs were determined based on literature references, knowledge within the LONGLIFE project and databases for LCA (Ecoinvent 2.0.) SimaPro 8.0.3 was used for the calculations. The data was further compared to an estimation of the environmental impact of a titanium dental implants as a reference, but data quality and specificity for the titanium implant was lower.

The total amount of CO2-eq in kilogram for the zirconium oxide implant was 1530g, which can be compared to the titanium implant that was estimated to 339g. When considering that the machining alone was responsible for over 90% of the emission of the zirconia implant manufacturing process, indicates that there is a large potential for further improvements to reduce the emission from the machining. It should further be kept in mind that a climate impact of 1500g of CO2-eq is not that much in a societal perspective. Driving 10 km in an average car would generate around the same amount.

WP5: Towards industrialisation

Highlighted results:
- The industrialization of a novel dental implant can be forecast in the near future,
- Other technical fields could benefit from the results of LONGLIFE.

Materials biocompatibility
The assessment of materials biocompatibility has been done for the intended use as ceramic for processing of implantable medical devices. An evaluation of biological safety – toxicology has been performed according to EN ISO 10993-1 and the directive 93/42/EEC, in particular cytotoxicity according EN ISO 10993-5 chemical analysis of organic contaminants according EN ISO 10993-18 and chemical analysis of elements according to EN ISO 10993-18.
The results of the evaluation are that the new materials do not affect the biological safety on the patients. This means that the material is safe to use for implants and is assumed to be biocompatible for this intended use, providing that the production process does not affect these initial properties.

Market analysis and prospects
KISCO started shortly after the launch of the project (before M36) a complete analysis of market and product issues for spine lumbar prosthesis. In the case of spine implants (mobile lumbar disks), there are uncertainties about future clinical trends and relatively modest market perspectives. Changes in the clinical consensus or the spine implant indication (cervical area for example) might however re-open the horizon within the next years.
On the other hand, data gathered today indicate that the overall market share of ceramic dental implants is expected to grow up to attain 5-15% in 2020, mainly in Europe and USA due to high average sales prices. The recent arrival of firmly established companies showed the vitality and trust which exists today in the development of dental ceramic implants.
In this context, the innovative and trustworthy option offered by LONGLIFE outcome is thought to be a key asset to take a consistent part of this market segment.
The perspectives concerning dental implants are optimistic, and the market release of a first generation of devices should take place within 24 months. Although less critical, these implants will also have to undergo thorough biological and clinical validation, which might affect their profitability regarding current ceramic and titanium implants. From the clinical viewpoint, the diffusion of these implants increases nowadays and interesting opportunities exists to industrialize new surface modifications, which is a very promising milestone for the future of ceramic implants in medical applications.

Last but not least, unforeseen applications have been proposed and prototyped, which could generate rapidly industrial activity at DMC.

WP6: Test set-up and long term assessment

Highlighted results:
- New protocols and strategies to test oral and spine implants were developed and could be used as a basis for a further improved version of ISO standards. More precisely, these new testing protocol are better suited to take into account the different degradation mechanisms and their interplays.

Assessment of dental implants
Task 6.1: Design of the test
For the long-term assessment of oral implants the partner UKL-FR developed an accelerated test set-up involving fatigue and (temperature) ageing (LTD), which are the two main mechanisms likely to be active in vivo. The objective of this task was to find a combination of fatigue and ageing so that the degradation of the components after the test matches as closely as possible the degradation in vivo but in an accelerated manner.
UKL-FR performed some adaptations to a commercially available artificial chewing machine. The machine with its eight conventional sample-holding basins received eight high-temperature basins in order to be able to increase the water temperature for the accelerated testing. The maximum temperature in the basins that could be obtained with water was 80°C around the embedded implants, the maximum loading frequency was 2 Hz and the applied load was 10 or 20 kg. The newly developed chewing simulator was assessed by testing commercially available zirconia implants (Y-TZP). Implants were either aged (only) or aged and fatigued under 10 kg of 20 kg. The results indicate that the applied experimental environment (80°C, water, for durations up to 2778 hours) led to a significant increase in the monoclinic fraction.
However, an additional influence of the applied load of 10 kg could not be observed. The results regarding the usage of the 20 kg load are difficult to interpret since a different m-fraction measuring set-up was used, but this load seems to increase ageing rates.

Task 6.2: Accelerated tests of implants
For the long-term assessment of oral implants, the partner UKL-FR exposed two sets of reference tetragonal zirconia polycrystal (=TZP) implants to the accelerated test set-up which involved fatigue and (temperature) ageing (see Deliverable D6.1). The objective of this task was to evaluate reference dental implants made from TZP regarding their resistance to degradation, i.e. low thermal degradation or tetragonal to monoclinic transformation. One tested implant set was a commercially available implant system and a second one was a TZP prototype implant system produced by one consortium partner (ANTHOGYR). The implants were installed in the adapted artificial chewing machine and loaded for different times/loading cycles and at different loads. The reference implants “ceramic.implant” showed an increase in aging/transformation when the cycles/time in 80°C hot water increased (up to 75% of mean monoclinic fraction at 10 million cycles). In contrast to these results, there was hardly an increase in mean monoclinic fraction when the ANTHOGYR prototype implants were tested (max. 9%). On the other hand, some ANTHOGYR implants fractured. The differences in ageing susceptibility and fracture resistance may be explained through differences in implant production methods including differences in design, powder composition, grain size, sintering process and machining of the implants, that globally lead to a a lower transformability of ANTHOGYR implants.
These results lead to revise the design of ANTHOGYR implants. Thus for further low thermal degradation behavior evaluation, two Y-TZP and six Ce-TZP implants with the improved design were aged and loaded in the artificial chewing simulator. They were submitted to up to 10 million cycles at 80°C in the chewing simulator. On the Ce-TZP implants, a new degradation mechanism was evidenced: the wear of the contact surface with the loading frame. The only detectable occurrence of phase transformation was on these "worn sides" where the antagonist hit the implant. There was no effect of aging and no effect of the load either (on the undamaged zones of the implants there was no m-phase detectable). The only sign of degradation was on the worn zone that contained up to 13% monoclinic phase. In spite of the lower strength of 12Ce-TZP as compared to 3Y-TZP, no implants fractured during these new tests. This emphasizes the quality of the new design. Unfortunately, the final version of LONGLIFE dental implants (final design with the LONGLIFE composite) was not assessed at the end of the project, because the implants were ready too late.

Assessment of spine implants
Task 6.1: Design of the test
The industrialisation and potential clinical use of the spine implants developed in LONGLIFE project are in particular subject to a complete confidence in their reliability over at least 60 years of use in vivo. To prove this reliability, a set of multiphysic characterization has been developed.
This test is conducted in two parts, combining fatigue, hydrothermal ageing and decoapatation on the first part (conducted at INSA), and dealing with wear for the second part. Both parts of the tests are conducted on the same implants, so that at the end of the tests these implants will have undergone solicitations equivalent to 60 years in-vivo.
1- Fatigue – Ageing testing (INSA-Lyon):
The ASTM F-2346 standard states loading configurations for fatigue tests on spinal implants. However, this standard is more specifically devoted to intervertebral disks, and not fully adequate to monoblock implants such as the ones developed in the project. Moreover, as described in the standard, “These test methods are intended to enable the user to mechanically compare artificial intervertebral discs and do not purport to provide performance standards for artificial intervertebral discs”. Clearly, testing our implants using only the tests described in the F-2346 standard is not enough to ensure the 60-years lifetime we aim at.
Thus it was decided to base our test on the standard, but not to follow all its recommendations and to go beyond. In particular, a decoaptation phase was introduced, that is not mentioned in the standard. Indeed, we believe that decoaptation phases may exist in vivo, and they are susceptible to deteriorate the bearing surfaces, thus to decrease the implants lifetime. Thus the test sequence is a combination of fatigue (at 12 kN and 5 kN, representing different postures, in diluted calf serum at 37°C), hydrothermal ageing and decoaptation (also in calf serum).
2- Wear testing (KISCO):
According FDA guidance “Preparation and Review of Investigational Device Exemption Applications (IDEs) for Total Artificial Discs” issued on April 11, 2008, wear testing method establishes durability, potential interdiscal height loss and stability. The wear testing involves cyclic loading that incorporates all directions of motion according ISO 18192-1(2011) as a worst case method. Samples should be tested simultaneously up to 10 Million cycles. Besides, wear debris are extracted according a specific filtering procedure, ISO 14242-2(2012), retained and numbered at each millions cycles. In addition, an analysis of particles from wear debris is performed according ASTM F1877-05(2010) characterizing morphology of particles from extracted wear testing fluid.

Task 6.2: Accelerated tests of implants
Two hybrid 3Y-TP-Ti, two full 3Y-TZP and two full Ce-TZP spine implants were tested using the multiphysic test. They underwent the cycles presented below in the Table 3.

Neither hybrid nor Ce-TZP implants did complete any sequence, because they broke in static conditions undor low loads or before10 million cycles of fatigue. This was related to the intrinsically low strength of Ce-TZP, combined with a too large clearance that concentrated the stresses in a weak part of the implant. For hybrid implants, this was a consequence of a bad adjustment.
Y-TZP implants completed the half test, equivalent to 30 years in vivo. Due to unforeseen time constraints it was not possible to complete the expected 60 years.
In the test used here, the most critical solicitations for spine implants seemed to be fatigue and decoaptation. Simple wear test only seemed to improve the surface roughness of the ceramic parts (of course, this is accompanied by the creation of wear debris that should be characterized). Hydrothermal ageing was rather limited, since the material used by DCM to machine the implants is rather stable. On the other hand, fatigue led to fracture, and decoaptation to severly damaged zones that could even prevent the implant to function normally, by impairing their movements.

These results were inputs for WP3 and WP4 and led to the definition of a new design of implants, more resistant to mechanical stresses. This new design could not be tested yet.

Also, the test proved to be discriminant between resistant and not-so resistant implants. It could be a base for an improvement of international standards on spine implants.

Physico-chemical characterisation
LONGLIFE project was also the occasion to progress on the assessment of tetragonal-to-monoclinic transformation in zirconia, and to compare the results obtained by two techniques: raman spectroscopy and x-ray diffraction.
It was shown that Raman Spectroscopy, especially coupled with imaging, is much more adequate to measure the monoclinic fraction on topographic samples such as dental implants. On the other hands, this technique is limited to the analysis of very small areas. For a more general view one will prefer to use x-ray diffraction (XRD). A new way of analyzing XRD data was also introduced during the project, enabling the analysis of concave samples (which was not previously possible).

Potential Impact:
A significant impact from the different results of the project is expected in the following technical areas, as highlighted already at the inception of the project. As a reminder, the strategy of LONGLIFE fits to the call ‘NMP.2011.2.1-1 Research and innovation for advanced multifunctional ceramic materials’. The activities of the proposal indeed included:
- Selection of one (or a limited number of) advanced ceramic material(s) that have the potential to add value to SMEs' products and sustainability to their industrial processes. This was the objective of LONGLIFE to ‘rejuvenate’ zirconia, which was introduced for total hip replacement but abandoned after unexpected failures. LONGLIFE has introduced new zirconia ceramics and composites for implants keeping the positive effect of phase transformation toughening but avoiding the drawback of hydrothermal ageing. These new implants will open new opportunities for the companies involved in LONGLIFE.
- Development of advanced added value ceramic materials that offer increased/simultaneous functionalities, e.g. biological interactions… The objective of LONGLIFE was to bring new functionalities (biological) to ceramic (zirconia) implants.

The modification of process strategies (i.e. nano-powder engineering to surface treatments), the involvement of one SME developing industrial design tools (AKEO+) and the industrial assessment of new implants were also in agreement with the call.

All these aspects are described in more details below.

Impacts in line with the work programme

(i) Increase of the knowledge-intensity of the SMEs’ production as far as material science and engineering are concerned: 5 SMEs participated in LONGLIFE in close collaboration with industrial and public research partners to devise new knowledge and strategies for material development and processes. The production of new nano-composite powders with improved synthesis methods, new surface treatments of ‘bioinert’ ceramics, and new implants perfectly fitted to ceramic specificities were the main aspects of LONGLIFE and are mow mastered by the companies involved in LONGLIFE. SMEs located in all countries of Europe hold a 20% market share of dental implants worldwide. Therefore, a European center for the knowledge of reliable ceramic dental implant could have long term benefit for the whole European sector by increasing innovation. LONGLIFE partnership can be a nucleus for such European center of expertise on ceramic dental implants, associating materials scientists, mechanical engineers, biologists and clinicians together with dental companies. It is to note that ANTHOGYR and INSA have created a common laboratory (LEAD : http://mateis.insa-lyon.fr/lead) at the end of the project.
(ii) Increase of the added value of future SMEs' products: new low-cost competitors, even in the biomedical field, challenge EU competitiveness worldwide. For example, zirconia blanks from China, ready to be machined by dental companies can be found on the market. The aim of the project was to bring new types of implants, with new designs and distinctive added value well beyond state of the art. LONGLIFE implants aimed to be original, reliable, and long lasting and they are. The most promising application and the most advanced concerns dental implants, for which the results at the end of the project are exciting. ANTHOGYR forecasts a future industrialization of dental implants based on the LONGLIFE strategy within a period of 2 years. The path might be longer for spine implants, for which the new EU regulations are clearly limiting the possible exploitation in the near future. These new regulations, still not fully finalized will increase costs and efforts to put spine products on the market, since they will be considered as Class III medical devices.
In the field of materials, the new synthesis route developed in the course of the project (so called post-doping route) is highly promising to process multi-phasic systems. This does not apply only to the composites developed in LONGLIFE. This new post-doping route could be exploited by a partner of LONGLIFE or by a future spin-off of POLITO.
(iii) Novel use of advanced materials: zirconia is the best oxide ceramic in terms of mechanical properties. This is the only oxide ceramic able to withstand very high loads for long periods without failure. LONGLIFE’s academic partners have a high-level, recognised expertise on zirconia materials. Their development new tough, strong and stable zirconia-based composites opens the door towards better spinal and dental implants in LONGLIFE, but also to major breakthroughs in industrial applications for which structural ceramics are needed. DMC already developed technical products from the LONGLIFE compositions, which could be launched in the market in the near future.

Scientific and technological impacts of the project

New ceramics with improved multi-functionalities.

LONGLIFE has optimally exploited the numerous assets that characterize stabilized zirconia. This leads to the development of new ceramic materials combining simultaneously very interesting properties that in the past have seemed to be somewhat mutually exclusive, such as high toughness, high strength and resistance to ageing. Combined with the strong bio-compatibility, which in turn leads to high bone integration, these properties will lead to more reliable and better performing ceramic dental and spinal surgerical implants.

LONGLIFE has shifted towards a new paradigm with a ceramic implant ‘for life’. In order to reach this ambitious goal it was absolutely necessary to produce zirconia based ceramic implants with superior degree reliability and a perfect stability in vivo. The results of LONGLIFE are meeting our expectations: with a toughness of about 10 MPa√m, a strength superior to 1000 MPa and a complete insensibility to LTD, the performances of the developed composites are among the best (if not the best) of all ceramics developed so far. Moreover, the pseudo-plastic behavior of the material leads to a reliability never reached so far with ceramics, with a value of Weibull modulus of more than 50 and plasticity before failure, almost as in metals.

The reinforcement of zirconia as a material for dental or spine applications, its higher reliability and improved ageing resistance are also expected to lead to the increased use of zirconia for other medical applications, despite the dramatic setback suffered following the series of failures of zirconia femoral heads around the turn of the century (the ‘Prozyr® affaire’). Indeed, the development of implants with improved tissue-integration is expected to lead in the medium term and long term to use zirconia for “new” types of implants in a wide range of fields (spine (for patients suffering from early onset obesity), hip, knee, shoulder, etc and medical devices (surgical tools, dialysis, etc).

Other important industries that could in principle benefit from the development of novel, tough, and ageing resistant stabilized zirconia materials are the aerospace and the electrical energy production industries. Zirconia thermal barrier coatings applied to the blades in turbines, for example, can suffer from ageing. Some of the fundamental insights and solutions proposed by LONGLIFE for dental and biomedical applications might in principle apply to thermal barrier coatings as well; this alone could be a very relevant impact in term of energy savings and decreased pollution, since more stable zirconia means higher operating temperatures of the turbo-engines.

In general, LONGLIFE implements a novel use of advanced ceramic materials, the novelty being in the holistic approach used, informed simultaneously by the requirements imposed by the biological environment and by the possibilities offered by the ceramic material.

New surfaces with improved biological functions
Several surface modifications methods were proposed and implemented in LONGLIFE, as it is the case of carbon coatings improving the wear behavior of bearing parts, nitrogen-doped hydrogenated amorphous carbon (a-C:H:N) coatings improving the antibacterial properties of zirconia, sandblasting and porous coatings improving the osseo-integration. The new LONGLIFE composite in form of a porous coating demonstrated good biocompatibility and was even superior to conventional Y-TZP or Titanium in terms of long-term attachment of mineralized hard tissue-specific ECM in the cell culture. In the animal investigation, this type of surface showed the highest implant-to-bone contact as well as the highest force values in Newton for push-in (highest biomechanical strength). As these coatings also exhibited the lowest amount of bacterial adhesion, they are likely to present the next generation of surfaces for improved dental implants.

Optimised methodologies for the in vitro assessment of implants

Key results of the project are the improved protocols for assessing a priori the long-term mechanical and biological performances of implants.

The first innovative approach of LONGLIFE has been to develop combined, “multiphysics” solicitations to devise relevant tests for implants. We did not want to repeat the errors committed with zirconia ceramics in orthopedics, partly due to irrelevant testing methods of hip joints before their clinical use. The consortium did not seek to follow ISO standards but to go beyond, by including all degradation mechanisms and their interplay. We have therefore developed in vitro testing combining aging and fatigue in the case of dental implants, and aging, wear, fatigue and micro-separation in the case of spine implants. Such extended protocols were never proposed before. The LONGLIFE approach will therefore certainly impact the biomedical community as far as dental and spine implant testing is concerned.
The second innovative approach of LONGLIFE has been to develop new in vitro biological testing of dental materials, mimicking to a larger extent than usual protocol the complexity of the oral environment. This was applied both for cells and microorganisms. Co-cultures were developed and gave results in line with further in vivo testing on animals. If confirmed in some future studies, the fact that co-cultures reproduce to a large extent the results obtained on animals, this would represent a major advance in the field of biomaterials testing. It would avoid (or at least decrease the number of) heavy animal studies prior to clinical use. Bio-reactor studies on implants themselves (instead of samples with inevitably different surface features) have also been developed and lead to more relevant testing. Last, The ex-vivo antimicrobial testing developed in LONGLIFE using human saliva will represent the realistic microbial situation within the oral cavity.

Numerical design of ceramic implants
The design of the LONGLIFE implants was optimized based on the specific nature of ceramic materials, thus leading to the further improvement of the implant reliability. The advances brought about by the Finite Element Analysis developed in LONGLIFE enables the end-user to develop faster and with a higher degree of reliability Zirconia implants. The design of new implants with Zirconia-based materials is more secure, way beyond standard “copy paste” designs from metallic materials.
An additional output of the LONGLIFE project is the definitive proof that mobile prostheses give additional values as compared to fusion devices. This was possible through a Finite Element Analysis of a multi-level spine model with the device and adjacent vertebraes and disks. Our results conclude that the use of mobile prostheses as developed in LONGLIFE lead to a decrease of 40% of stresses in the adjacent levels for the same degree of mobility, when compared to fusion cages. In order words, LONGLIFE mobile prostheses would restore the mobility of the damage disk without compromising the lifetime of the adjacent disks as it is generally encountered with fusion devices.

Insight into the governing mechanisms of implants degradation

Insights into these mechanisms are one of LONGLIFE’s outcomes. A sound interpretation of the ageing phenomena in stabilized zirconia at the micro- and submicrometric scale represents a key contribution to a long lasting debate in the scientific community, and leads to strategies for engineering the stabilization properties and avoid ageing. The different degradation mechanisms of implants and their interplays are better known than before.

Innovative processing route of ceramic nano-composites
As described in the report, an innovative processing route able to tune compositional and microstructural features of zirconia-based ultra-fine composites has been developed in the course of LONGLIFE. We indeed developed an alternative method to produce alumina- and zirconia-based composites, inspired on the concept of “surface modification” of commercial oxide powders, which shows some progress with respect to previously developed techniques. In fact, in our process, only inorganic precursors and aqueous media are used, making this strategy much more simple and potentially transferable to a pre-industrial scale production. A second difference lays in the mixture drying method, which we perform by means of a “flash” drying technique, such as atomization, in which the liquid medium is converted into fine droplets and instantaneously evaporated. This step has a key role in the process, since the homogeneity of the mixture is “frozen” in the dried products, completely avoiding the segregation of the metallic dopants, as can occur by slow drying in an oven. The method was successfully applied to the elaboration of zirconia-based composites with complex compositions and microstructures, containing both equiaxial and elongated second phases.
The process developed in the frame of LONGLIFE has been registered as an Italian Patent (TO2014A000145, registered on 21 February 2014) and expanded to a PCT.

European competitiveness and economic growth thanks to the project

Dental implants have a share of approximately 20% of the entire dental device market, and they are expected to have the highest growth rate. At the beginning of the project, ceramic (Zirconia based) implants represented less than 1% of this total market. Given reliable and highly osseo-integrating implants, the market share is expected to grow up to attain 5-15% in 2020, mainly in Europe and USA due to high average sales prices. The recent arrival of firmly established companies (such as Metoxit, Straumann) shows the vitality and trust existing today in the development of dental ceramic implants. LONGLIFE aims at significantly contributing to build a nucleus of European medical technology specialists in the field of dental implants, both of which are rapidly growing markets worldwide. The launch of a Ceria-stabilized zirconia based implant by ANTHOGYR will present a major innovation in the field and will contribute to strengthen the leading position of Europe at the time when Asia is pushing hard into the market. The European market for medical device technology is the world’s second largest (US: 37%, EU-15: 26%, Japan: 15%) and was valued at 41 billion euro in 2002. In recent years, the sector has suffered losses in world market share and employment, mainly due to market consolidation and significantly lower European expenditure on healthcare (5.7% of GDP in EU-15 compared to 13.9% in the US and 7.1% in Japan). The global dental implant market, including Europe, the US, and the Asia Pacific, was valued at $2,611.5 million in 2008. Europe held the largest proportion of the total revenues, garnering 55.8% of global dental revenues. The US followed with $638.3 million. The prevision is the expansion of the worldwide market at a compound annual growth rate of 8.2%.

More specifically, the market for dental implants worldwide is estimated for over 2.1 billion Euro, and producers inside the EU and Switzerland cover over 30% of the total turnover worldwide. Oral titanium implants have a share of approximately 20% of the entire dental device market. Since only 2-3% of the edentulous and partially edentulous patients have implants, there is an enormous potential for the industry to grow. The share of Zirconia-based ceramic implants was only ca. 1% at the beginning of the project, but given the development of Zirconia-based crowns and bridges, taking now up to 50% of the market, this share may rise to 15% within the next 5 years.

In order to capitalize on and contribute to this opportunity, it is absolutely necessary to produce ceramic implants with the same reliability and stability as Titanium, and with a higher degree of biocompatibility and esthetics, what was an objective successfully tackled by the partners of LONGLIFE .

European competitiveness will potentially be bolstered by additional LONGLIFE results, such as knowledge-based insight from FEM calculations, which should reduce the cost to market of ceramics implant technology by reducing trial and error experimentation. Indeed, FEM provides for the reduction of the numbers of prototypes and tests needed to validate new implants.

LONGLIFE partners have developed well-thought out strategies to take advantage of the market opportunities described above.

Societal implications of the project

The antimicrobial and osteo-conductive zirconia surfaces associated to high performance materials will lead to the industrial development of zirconia implants with increased lifetime, which will contribute to a decreased risk of infection, less implant failure, and thus healthier patients and a decreased cost for the health system, as no revision surgery will be required.

LONGLIFE thus participates in preventing a repetition of the "Prozyr" affair, a repeat of which would have a tremendous (societal and financial) impact if thousands of people should be summoned in hospitals and in dental laboratories to be told that the components that were implanted in their body were defective.Not only LONGLIFE helps preventing societal and financial burdens, it also brings about concrete, real progress: oral implants obviously improve the lives of many patients and offer an effective treatment for partially and totally edentulous patients with best mechanical guaranties and aesthetic results.

The advantages brought about by LONGLIFE spinal implants are critical as well, even if changes in regulations have dampened our effort to industrialize a product at the end of the project. We have however shown that ceramic mobile prostheses would provide a better mobility with less stresses on the adjacent levels, providing for a better reliability, a better quality of life and allowing more patients with spinal problems to lead more “active” lives, thus decreasing social security costs. In addition, an all-ceramic lumbar disk implant would limit debris generation, allow MRI monitoring, thereby easing the post-surgical treatment and monitoring of patients. The absence of toxic degradation improves patient health over a longer term.

Dissemination

The LONGLIFE dissemination plan generates an effective flow of information and publicity about the objectives and results of the project, contributions made to European knowledge and scientific excellence, the value of collaboration on a Europe-wide scale, and benefits to EU citizens in general to promote the socio-economic impact of the research.

Global framework of communication

In addition to company use of findings and patents issued from the cooperative work, a global framework has been defined to communicate as broadly and economically possible all of expected results and foster new usages and ideas in many countries in the world in addition to European ones. Experience shows the need to use multi-canal approach, meaning the use of media relation, in addition to internet presence, forum and boots presence, … enriched by solid substance and attractive shape as highlighted in following points.

KISCO was in charge of setting up of the LONGLIFE website and updating it regularly. Moreover, a simple and attractive logo plus a simple communication chart have been defined to ensure instant perception of expected innovation and breakthrough. The LONGLIFE logo produced at the beginning of the project has been used in all documents related to the project (deliverables, website, communications, leaflet…).

Dissemination to the general public

The project aims and results have been published in the lay press, in scientific pages of daily newspapers, as well as in advertisements for the dentists and physicians. A video of the projects achievements has been made and will be available on the website and distributed to targeted possible end-users.

Dissemination to the scientific community

New knowledge has been disseminated in the form of publications, contributions and participation at international conferences, workshops and summits, industrial fairs.
LONGLIFE partners published in major international journals in the materials and biomedical fields (see Section1.2)

Joint meetings of LONGLIFE partners with investigators from other labs/companies in the field of materials, surface science and implants has been organized to share information on common aspects of ceramic development, surface modifications or implant-tissue interfaces. One workshop has been organized focusing on ‘zirconia as a structural and biomedical ceramic’ with members of the Scientific Advisory Board who are at the cutting edge of their respective fields.

LONGLIFE also participated actively to the Summer School ‘"Ceramic and Glass Science and Technology applied to bioceramics and bioglasses" in June (17th-19th) 2015, in Madrid, as one of the main organisers. 80 young scientists attended the Summer School, which was organized the week before the 14th Conference of the European Ceramic Society Meeting, gathering more than 1.000 scientists from over the world. Participant students or young researchers were invited to present a poster on their own research work and to prepare some points to be discussed during a special "Questions/Answers session" organized with small groups of students and teachers working in the same field. LONGLIFE took the lead on the aspects related to the ‘Inert ceramics’ for orthopaedic and dental applications. Lectures from partners of LONGLIFE were done. Brochures and leaflets distributed to the participants helped to communicate on LONGLIFE strategies and main outputs.

LONGLIFE partners promoted the organization of sessions on selected conferences where the results of projects are displayed to large audiences. The recognition of Prof. Chevalier, Montanaro, Sergo, Kohal in the field of ceramics and dental implants and their presence in symposium organizing committees ensured opportunities to organize specific sessions in international conferences, such as the European Society of Biomaterials, E-MRS, European Ceramic Society.

Dissemination to the industry

LONGLIFE research aimed at creating new solutions that contribute to the trend of increasing the quality and longevity of treatments at falling prices, which is of key interest to medical sciences and the industry. Therefore, LONGLIFE has been disseminated (while also being protected and exploited) in the scope of patents, technology transfer, collaborations and licensing. Presentation of results at trade shows occurred in order to raise technology profile awareness.
In addition to the points mentioned above, application of results for patents and contacting important industrial branches will keep facilitating the dissemination to the industry.

Exploitation

LONGLIFE partners have developed well-thought out strategies to take advantage of the market opportunities. The exploitable foreground is described in Section 1.2.

List of Websites:
The address of the project public website is given on the front page of this report:
http://longlife-project.eu

The main contact is the project coordinator: Prof Jérôme Chevalier, INSA-Lyon.