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Silicon Nitride Coatings for Improved Implant Function

Final Report Summary - LIFELONGJOINTS (Silicon Nitride Coatings for Improved Implant Function)

Executive Summary:
Total Joint Replacement (TJR), particularly of the hip (THR) and also the knee, represents one of the most successful and common musculoskeletal, indeed any, surgical intervention, bringing about quantifiable benefits to individual patients and society as a whole. This success has led to an unprecedented rise in the number of procedures being undertaken. Specifically, both the original patient group (elderly with osteoarthritis) has expanded and new cohorts including different disease states, high body mass index recipients and younger patients are increasingly being treated with THRs. These have led to a higher rate of revision surgery which places additional demands on the healthcare systems over and above the original primary procedure. These re-operations arise primarily from the wear where particular debris and ions react with the local tissues causing inflammation, generation of pseudo-tumours and tissue wastage depending on the exact nature of the materials involved. This project aims to overcome some of these problems by the creation of a high wear coating in which any debris that is formed dissolves into harmless ions, thus reducing the potential harmful effects of the particles in the joint space. The project was split into 7 work packages.

WP1: Coatings deposited at Ib and LiU were characterized by XPS in terms of composition, SEM in terms of microstructure, and nanoindentation was used to determine hardness and reduced Young’s modulus, All coatings showed a Si/N ratio within the specification limits. The coatings belonging to groups 1, 2, and 3 show an under dense and columnar microstructure under cross-sectional SEM, while the coatings from group 4 showed a dense and featureless structure. This resulted in significantly better mechanical properties of coatings from group 4 over all the other coatings.

WP2: Novel 6 station and 1 station simulators were designed and manufactured that exceed specifications for existing simulators and the performance required by the international standard ISO 14242-1. These simulators were validated using traditional polyethylene on metal hip components and then progressed to testing on SiN coatings and differing activities of daily living. A new particle isolation technique was developed that was the subject of a European CEN workshop agreement - CWA 17253-1. New methods for the testing of corrosive characteristics were developed. Assays demonstrated that SiN did not produce adverse reactions in both cell-lines and primary blood cells. Further, use of the SiN coating demonstrated a reduction in the ion release compared to metallic surfaces.

WP3: LTHT has delivered an unprecedented patient dataset of kinematics and kinetics. The dataset has proven to be a good foundation for the validation of the whole-body modelling framework, for the definition of severe loading scenarios for physical wear simulators, and for a comprehensive understanding of the role of critical patient-specific parameters on joint loading. The dataset is unique in the world for both the size of the measured group (>150 patients) and the broad assortment of activities of daily living that were measured. Simulated hip contact forces (HCF) have been comprehensively validated. The simulated data was based on the measured patient activities in the LTHT dataset. Results showed good agreement between in-silico simulations and experimental data following extensive improvements to the model muscle description. The resulting improved and validated model is part of the public AnyBody Model repository.

WP4: Extensive production of the SiNx coatings for the testing and assessment. Further, the HIPIMS equipment was up-scaled from an academic to industrial environment couple with Industrial qualification of the manufactured equipment and Operational and Performance qualifications of Silicon Nitride coating. Further investment will be made in delivering a coating of high quality.

WP5: This work package concerned itself with the in vivo assessment of the silicon nitride coating. These results confirmed the SiNx biocompatibility when compared to CoCr, the material often used in joint replacements. There was no tissue reaction evident in areas where SiN particles resided and were similar in appearance to control specimens.

WP6: This work package was focused on the dissemination and exploitation of the results within LifeLongJoints. Highlights include:

• Two CEN workshop agreements: CWA 17253-1 and CWA 17253-2.
• The commercial delivery of simulators within the UK and abroad.
• The transfer and enhancement of models and data in the AnyBody Repository.
• The development of HiPIMS technology and its installation.

In addition, WP7 (Management) continued to provide leadership and management for the Consortium including the organisation of the Technical Management Committee, which is the principal operational body of LifeLongJoints, as well as the Partner Assemblies.
Project Context and Objectives:
Total Joint Replacement (TJR), particularly of the hip (THR) and also the knee, represents one of the most successful and common musculoskeletal, indeed any, surgical intervention, bringing about quantifiable benefits to individual patients and society as a whole. This success has led to an unprecedented rise in the number of procedures being undertaken. Specifically, both the original patient group (elderly with osteoarthritis) has expanded and new cohorts including different disease states, high body mass index recipients and younger patients are increasingly being treated with THRs. For instance, THR has increased from 50 cases per 100,000 person years in the early ’70s to 145 per 100,000 this decade in the US and UK.

Through considerable advances in technologies, surgical techniques and rehabilitation short-term adverse events, such as infection, have reduced markedly. Even with failure rates as low as 5% at 10 years, the sheer number of primary operations (>1.5 million globally for hips and knees) means that the estimated number of revision procedures is about 50,000 in the EU alone at a cost of €500M in healthcare expenses. These salvage procedures are expensive, complex and have lower success rates than primary operations, impacting both on the morbidity of the, by then older, patient and the cost-conscious healthcare system. These longer-term failures are largely the result of device loosening secondary to wear of the bearing. For younger, hip replacement patients the need for longer wearing and robust bearings resilient to adverse loads is paramount in order to avoid multiple surgical interventions for TJR during their lifetimes. This requirement has to be positioned within a heightened regulatory regime due to the well-publicised, high failure rates within contemporary metal-on-metal hip and resurfacing prostheses, in which the regulatory authorities and professional bodies have acted to ban or significantly curtail the use of these prostheses and increase surveillance of those already in use.

LifeLongJoints: Aims and Objectives

In response to these challenges LifeLongJoints was designed to deliver next-generation, functional Silicon Nitride coatings for articulating surfaces and interfaces of total hip replacements (THR) that produce longer lasting implants. New solutions to these issues are required and are addressed in this project, in a multidimensional manner realising that the issue of wear has to be tackled with a material property combination that is low-wearing, produces debris that is soluble, which does not elicit an inappropriate biological. This combination of attributes moves away from focusing on developing extremely low wear systems in isolation, to one that takes a more holistic view of wear in THR looking at all stages in the failure process. These improved wear characteristics will lead to: (1) improved therapeutic outcomes through longer lasting; and, more robust implants and (2) overall improvements in the quality of life of the patients through reductions in implant failures and subsequent revisions. This will significantly reduce the risk of implant failure associated with wear, synergistic wear/corrosion processes and the resultant debris release as well as provide significant economic and societal benefit to Europe and its citizens; and, will be supplemented by advances in the way hip replacements are tested using both mechanical simulators and computational models.

The seven objectives for the programme are:

1. Development and characterisation of a novel wear-resistant silicon nitride-based coating for both articulating (hard-on-hard and hard-on-polyethylene) and non-articulating bearing surfaces for three key bearing/interface applications (work packages (WP) 1 to 5);

2. Development of advanced simulation methodologies, in-vitro, together with the dissemination of new guidance documents and standards for the functional assessment of the novel silicon nitride coatings (WP1, 2 and 5);

3. Production of in-silico tools for the prediction of wear across the pertinent parameter space that reflects the variability in patient and surgical inputs with which to evaluate coating performance (WP1, 2 and 3);

4. Production and pre-clinical testing of a series of prototype devices in each of the scenarios for the purposes of functional assessment and production evaluation, particularly the use of adverse conditions early in the assessment cycle (WP2 to 5);

5. Finalise manufacturing scale-up through the translation of coating technology from a research to the industrial environment (WP1, 4 & 6);

6. Delivery of the necessary in-vivo data through the use of animal experiments to support the application of the coating in terms of cytotoxicity and joint functionality; and,

7. Deliver the necessary regulatory evidence that is aligned with 93/42/EEC, to an advanced stage. (WP1 to 7).

Three different interface scenarios are targeted each with its own unique target profile:

• To reduce polyethylene wear - The Silicon Nitride coating to be applied here has the potential to reduce long-term UHMWPE wear, due to increased resistance to third body damage and scratch resistance compared to CoCr counterfaces, as well as possible improvements in lubricity.

• To reduce wear in metal-on-metal (MoM) surface replacements - Wear-associated ion and nanoparticle release is a direct consequence of surface wear and tribocorrosion. It is predicted that the application of the Silicon Nitride coating against Silicon Nitride counterfaces will substantially reduce the production of such particles (through wear) and ions (through corrosion of either the bearing surface as it is activated by wear or by dissolution of wear particles) leading to reduced adverse biological responses and enhanced biocompatibility of these devices.

• To reduce corrosion/wear at taper junctions - Taper junctions between the femoral neck and head have been identified as having increased wear in different bearing combinations (for instance, metal-on-polyethylene; metal-on-metal) as a direct result of fretting due to micromotion and crevice corrosion between either similar (CoCr/CoCr) or dissimilar (Ti/CoCr) metals, which has been associated with a “rocking” and torsional phenomenon. This issue has been highlighted by the increasing use of larger (>32mm) heads and there is an indication that the amount of wear and corrosion is positively correlated with head size, and induced frictional torques. Silicon Nitride coatings on one or both sides of the interface may have the ability to reduce the production of CoCr debris, reduce corrosion and possibly influence the locking mechanism.

LifeLongJoints Consortium

The Consortium comprises 15 partners, which in their own right are centres of excellence within the European research and technology transfer landscape. The Consortium is experienced at delivering collaborative projects over extended periods (4 years) with significant investment (>€2M), including the current SPINEFX and VPHOP grants. Each partner brings a set of skills and/or expertise that, when developed within the Consortium, offers the opportunity for significant advances in the underpinning coating technology and the adjunct pre-clinical testing regimes for devices which comprise these coatings and those more generally. No two partners bring to the Consortium the same primary skills set.

Expected Impact

1. LifeLongJoints will develop a new Silicon Nitride low wear coating which, for the first time, produces soluble debris with the potential for substantially reduced effects on the biological system and, hence, lower failure within the hip replacement.

2. Advanced assessment procedures including novel membrane assay systems, beyond the state of the art simulator and an enhanced testing framework which will be utilised for predicting wear/corrosion performance in-vivo.

3. Increased competitiveness of European Industry – delivered through both improved product performance through the coating and enhanced testing.

These expected benefits if successful could lead to improved therapeutic outcomes and increased patient benefit.
Project Results:
This final report outlines the activities and results delivered on a work package by work package basis, as set out in the original Description of Work.

1. WP1 - Synthesis and Characterisation of Silicon Nitride Coatings

Aims, deliverables and tasks of WP1

The purposes of Work Package 1 were:

• The development and specification of high power impulse magnetron sputtering (HiPIMS) processes for the deposition of silicon nitride - (SiNx) coatings;
• The production of functional prototypes of SiNx coated cobalt chromium discs for bench testing, research prototypes of SiNx coated femoral heads, sockets and hip prosthesis tapers; and,
• Material analysis of commercial coatings and studies of wear mechanisms.

All set objectives and deliverables of WP1 were fulfilled.

Highlights from WP1

Year 1 - In Year 1, two deliverables, D1.1 and D1.2 were due and delivered, in M3 and M9, respectively. D1.1 consisted in “Preparation of the preliminary specification of coating deposition parameters for depositing SiNx coatings”, mainly based on earlier work by partners in WP 1 (UU and LiU), and D1.2 on the “Preparation of functional prototypes of a SiNx coated cobalt chromium discs for bench testing”. These processes focused on the deposition of ~ 7.5 μm thick SiNx, intended to meet the target specifications for the deposition of SiNx on metal-on-metal implants. Additionally, HiPIMS processes were developed for the deposition of SiNx coatings with a thickness of 3 μm - 4 μm on femoral heads of metal-on-polymer implants as well as on taper junctions.

Approximately 150 deposition runs were performed, focusing mainly on: i) effects of different global deposition process parameters for the magnetron sputter process; and ii) process development to facilitate the transfer to industrial standards, in terms of process controllability, reliability and the SiNx deposition on complex shaped structures.

Overview of main results:

Increased pulse energies and substrate temperatures (Ts) resulted in coatings with a featureless morphology, implying advantages with regards to mechanical performance and corrosive properties. Increasing N contents yielded increased hardness, elastic modulus, reduced corrosion, residual stress and wear. Coatings with thicknesses of approx. 4 μm showed satisfactory adhesion (ISO1/HF2 or better), while thicker coatings of approximately 7.5 μm showed insufficient adhesion (ISO2/HF3 or worse) based on Rockwell C tests.

Increased deposition pressures improved the coating adhesion (both in terms of scratch tests and Rockwell C) due to reduced residual stresses but required higher substrate temperatures to achieve a featureless morphology.

Potentially favourable HiPIMS processes with regards to coating properties and performance for 3-D objects were confined and specified by LiU – this consisted of advancement towards D1.3 (due M21) – and included the following process steps: pre-heat treatment at 3kW; argon etch; deposition pressure at 400 mPa, N2/Ar flow ratio of 0.28 pulse frequency (400 Hz) and energy (5-10 J / 2000-4000 W); table rotation; 2 targets and a full batch load.


Year 2 - The following deliverables were delivered in Period 2:

D1.3: Preparation of functional prototypes of a SiNx coated femoral head for use in a PE/Hard bearing scenario.
D1.4: Preparation of prototypes of a SiNx coated femoral head and socket for use in a hard/hard bearing scenario.
D1.5: Preparation of prototypes of SiNx coated taper for use in a hip head-stem scenario.
D1.6: Delivery of an intermediate coating specification.

Overview of main results:

Deposition parameters that were believed to have to be adapted to facilitate a translation between the two commercial sputter systems used in the project (the one at LiU and the one at Ib) were found to have no, or a beneficial effect on the coating properties (D1.6). LiU transferred an intermediate standard process as described in D1.6. Coatings with a good adhesion could be produced (ISO1/HF 2 or better), by the use of a CrN interlayer and optimized pre-treatment processes as well as optimized deposition parameters, resulting in low particle energies (D1.6).

N2 gave better adhesion than NH3 as precursor gas (D1.6). NO2 could be used as a precursor to obtain SiON films, where the O/N-ratio was determined by the pulse energy. Coatings with a similar or lower dissolution (corrosion) rate than CoCrMo alloy can be produced. Higher nitrogen contents in the coating result in slower dissolution rates.

Wear debris from SiNx coatings, were produced in a ball-on-disc setup and characterized, showing agglomerates between 0.15 and 2.0 µm, with individual particle sizes between 0.01 to 0.5 µm. Similar model particles are commercially available, and were found to dissolve in an aqueous environment, as expected.

Year 3 - The following deliverables were delivered in Period 3:

D1.4: Preparation of prototypes of a SiNx coated femoral head and socket for use in a hard/hard bearing scenario. Due M24, delivered M38. As previously mentioned, the delay in delivery was a result of a delayed design and in delivery of sockets for coating (M33), as well as cutting of the coated parts (M36).

D1.7: Preparation of research prototypes for testing in each prototype of the three stated scenarios. Due M36, delivered M38. The slight delay was due to a delay in deliver of sockets for coating (M33), as well as cutting of the coated parts (M36), as for D1.4.

D1.8: Material analysis of commercial coatings from WP4 and studies of wear mechanisms in WP2, was also worked on extensively during year 3 (DM57).

Overview of main results:

SiNx coatings with an excellent adhesion were obtained, displaying Rockwell indentation Class 0-1 and Lc2’s in scratch tests of approx. 40N. The excellent adhesion (measured in 2D) was the result of development work including a CrN interlayer, optimization of pre-treatment processes as well as an optimization of the deposition temperature. SiNx coatings were deposited onto 3D implants, of all three types identified in the project as relevant and important, i.e. CoCr hip heads and cups as well as Ti-6-4 tapers.

The 3D deposition procedure was found to be highly repeatable for coatings of >5.5 μm thickness, with a compositional variation of less than 10% between deposition runs and a thickness variation of less than 20% between deposition runs. Reciprocal wear tests of 2D SiNx coatings against Si3N4 balls, displayed similar or lower coefficients of friction than for CoCr, and a much lower specific wear rate of the coatings, down to an order of magnitude lower than for CoCr against Si3N4 (Fig. 6)

Year 4 - The main focus of Year 4 was on material analysis of commercial coatings from WP4 as well as supportive coating development. This work resulted in recommendations to WP4 on routes towards adjustment of deposition parameters to improve coating properties. In particular, results from 2D wear testing in combination with the results from the WP2 simulator testing contributed to the theory on the need for a high nitrogen content also in the interlayers in order to avoid preferential chemical reactions taking place, eventually leading to coating failure in a tribological situation. An investigative track in WP4 on the addition of C to the coatings was also preceded by the work undertaken within this WP.

Overview of main results:

Tailoring of the residual stresses in the coatings resulted in excellent coating adhesion (ISO 0/HF1) and a low surface roughness of 14 nm for coatings deposited on CoCrMo (with LiU system).

Carbon contents up to 20 at.% in SiCN could be achieved, also showing an improvement in the mechanical properties of SiN in some cases. This holds both for the HiPIMS/DCMS co-sputtered films (Fig. 8) and films synthesized with acetylene as the carbon source, (deposited in LiU system). This knowledge was transferred to WP4.

The commercial coatings (deposited with Ib system) had a consistently high nitrogen content over the year (48-52%), likely positive for a lower dissolution rate, as observed in Year 2 and reported in D1.8

Coatings designed for the final application (in the Industrial Ib system) had scratch test results above the defined target value (>40N). Most coatings performed well in 2D wear tests, giving lower wear rates than CoCr against Si3N4 and low PE wear rates. However, some of the coatings failed and this was further investigated in year 5.

Year 5 - The main focus of Year 5 was on material analysis of commercial coatings from WP4 and delivery of D1.8 (Material analysis of commercial coatings from WP4 and studies of wear mechanisms in WP2), (due month 57, delivered month 60), as well as supportive coating development. This work resulted in recommendations to WP4 on routes towards improvements of deposition parameters as well as better end coating properties. In particular, results contributed to the theory on the need for a higher coating density. The work in this year will result in a significant amount of publications also after project end.

Overview of main results:

Coatings deposited at Ib were characterized by XPS in terms of composition, SEM in terms of microstructure, and nanoindentation was used to determine hardness and reduced Young’s modulus, In terms of deposition process, the coatings were separated in 4 groups: (1) SiNx coatings deposited at relatively lower HiPIMS power, (2) SiCNx coatings deposited using Acetylene (C2H2) as reactive gas, (3) SiNx coatings containing Cr or Nb coming from a metallic target operated in DC mode, and (4) SiNx coatings deposited under a relatively higher HiPIMS power. All coatings showed a Si/N ratio within the specification limits. The coatings belonging to groups 1, 2, and 3 show an under dense and columnar microstructure under cross-sectional SEM, while the coatings from group 4 showed a dense and featureless structure. This resulted in significantly better mechanical properties of coatings from group 4 over all the other coatings.

The HiPIMS process to deposit SiCN coatings with Acetylene was transferred to Ib. In parallel, further studies on variations of the HiPIMS process were continued at LiU using a SiC target. Combinatorial sputtering was used to show that also SiFeCN coatings with high mechanical properties (E > 200 GPa, H > 14 GPa) and good biocompatibility can be produced.

Processes for deposition of 3D coatings, involving rotation during the process, need to be appropriately optimized in order to achieve a high density of the coatings, needed for lower reactivity and lower dissolution rate. A high coating density is crucial for the investigated system, in order to achieve functional properties in the final application, with an adequate tribocorrosive response. Relatively long tribocorrosive tests are needed to detect this.


2. WP2 - In-vitro Simulation and Biological Assessment of Wear in Silicon Nitride Coatings

This WP was concerned with the functional assessment of the prostheses coated with the SiN or its derivatives for both wear and wear/corrosion. As noted above three scenarios were conceived – hard on hard systems, hard on polymer and non-articulating interfaces. The majority of the activity was undertaken at SIMSOL (design and build of the simulators), UNIVLEEDS (simulator and corrosion testing) and TUHH (non-articulating interfaces). Significant interactions were undertaken with WP3 (testing profiles) and WP4 (acquisition of samples).

The Objectives for WP2 were:

O2.1 - Development of new generation functional hip wear simulator to allow simulation of more realistic scenarios including those challenging to implant bearing surfaces.
O2.2 - Development of novel particle analysis methodologies including cytotoxicity assays for Silicon Nitride particles.
O2.3 - Development of protocols for functional assessment of corrosion and taper micro-motion/damage within total hip replacement.
O2.4 - Comprehensive wear analysis of Silicon Nitride coated prostheses undertaken using adverse and standards defined conditions undertaken.
O2.5 - Investigation of corrosion processes within bearing surfaces and modular junctions of THR utilising silicon nitride coatings.
O2.6 - Investigation of cellular response to Silicon Nitride particle/ion.

All deliverables were completed.

Simulator technology

Currently multi-station hip wear simulators are available from three main manufacturers: MTS and AMTI, both US manufacturers, and Simulation Solutions, based in Manchester, UK. The simulators available from MTS and AMTI use servo-hydraulic actuators whilst Simulation Solutions use electro-mechanical servo motors for driving the axes of their simulators. Essentially the simulators conform to current hip standards in particular ISO 14242-1. The specification for the new generation simulators was developed to go beyond this state of the art with capabilities for a range of activities of daily living including stumbling and stair climbing built into the design. The two simulators conforming to this specification were produced in LifeLongJoints and have been a commercial success being sold in the UK and Within the ISO specification of the loading and displacement parameters for wear-testing total hip-joint prostheses there is an allowable displacement error of +/-3° at the maxima and minima of the motion on each axis and an error of +/-3% of the maximum force value at the maxima and minima of the axial loading waveform. The simulator performance was first checked against this standard to ensure ISO wear testing in this simulator is achievable. This was deemed to be successful with excellent following of the demand load/motion. Other non ISO 14242-1 motions/loads including the medial-lateral force demonstrated equally good performance.

Specification / Performance

Specification 1 - The Prosim LifeLongJoints Adverse Wear Hip Simulator meets the apparatus requirements set out in ISO 14242-1 (2012) Implants for surgery – wear of total hip-joint prostheses – Part 1: loading and displacement parameters for wear-testing machines and corresponding environmental conditions for test; Performance achieved - Motion and load following of the simulator is superior to that required for testing to the ISO 14242-1 (2012) standard.

Specification 2 - Each station is equipped with its own six axis load cell to allow in-test friction data to be collected; Performance achieved - Yes

Specification 3 - Axial loading, with a range of 0-8kN, is independently applied to each acetabular cup; Performance achieved – Yes

Specification 4 - Flexion-Extension motion range of +/-61° from vertical (femoral head motion) with all stations linked; Performance achieved - Yes

Specification 5 - Abduction-Adduction motion range +10° (adduction) to - 25° (abduction) from vertical (femoral head motion) with all stations linked; Performance achieved - Yes

Specification 6 - Interior-Exterior rotation range +/-40° (femoral head rotation) with each station individually driven; Performance achieved - An extended range of +/-45° is possible

Specification 7 - Force and displacement controlled Medial-Lateral Micro-separation with a range of 0-1.5kN and displacement of +/-5mm; Performance achieved - Displacement sensor range is +/-5mm. Maximum force is 1.5kN medial force on the cup. Lateral movement of the cup is not possible due to the presence of the femoral head.

Specification 8 - up Inclination Angle adjustment from 30° to 65° in 5° increments; Performance achieved - Cup can be adjusted from 0° to 65° in 5° increments.

Specification 9 - Cup Retroversion-Anteversion Angle adjustment from +30° to -30° (continuous); Performance achieved – Yes.

Specification 10 - Machine cycle speed: programmable 0.5Hz - 2.5Hz; Performance achieved – Yes.

Specification 11 - Each test can be any combination of up to 50 different movement and loading profiles so as to simulate typical activities of daily living; Performance achieved – Yes.

Biological Assay Development

In this task describes the development and optimisation of methodologies for the isolation and characterisation of very low volumes of Silicon Nitride (SiN) wear debris from serum containing lubricants from simple configuration and hip simulator wear testing. A method utilising sodium polytungstate and density gradient ultracentrifugation has been developed, which is capable of isolating very low volumes of wear particles, in the order of 0.03 mm3 per million cycles, which is equivalent to the lowest wear volumes recorded for modern composite ceramic–on-ceramic hip bearings. This represents a 10-100 fold increase in sensitivity compared to existing particle isolation methodologies. The new method is also remarkably sensitive demonstrating >75% recovery rates of spiked SiN particles and has been shown not to alter particle size or morphology. The method has been used to successfully recover both model SiN particles and SiN particles generated in serum lubricants in pin-on-plate wear tests. In addition, the methodology has also been demonstrated to successfully isolate cobalt chromium (CoCr) and zirconia toughened alumina (ZTA) ceramic particles, demonstrating the wide functionality of the method. This was the subject of a European CEN workshop agreement - CWA 17253-1.

In addition, this task optimised a suite of cellular assays designed to assess the in-vitro biocompatibility of SiN particles in a range of different cell types (fibroblasts, macrophages). These assays include cell viability, inflammatory responses, membrane toxicity and DNA damage (genotoxicity). To date all methodologies have been optimised with commercially available model SiN (<50nm), alumina ceramic and cobalt chromium particles. Cell viability assays optimised include MTT and ATP-Lite assays, which to date have shown that SiN particles are not toxic to cell lines or primary cells even at high concentrations which are unlikely to arise in-vivo (50 µm3 per cell). This is in contrast to the cobalt chromium control particles, which cause adverse cell responses at medium (5 µm3 per cell) and high doses (50µm3 per cell). In addition, comet assays also show that SiN particles do not affect DNA integrity, whereas CoCr particles show adverse effects on DNA with high particle concentrations after 24h and medium concentrations after 48h. Similarly SiN particles failed to elicit a significant elevation in inflammatory cytokine release in primary macrophage cells, in contrast to the CoCr particles, which caused significantly higher levels of TNF-α to be released after 24h. Novel membrane toxicity assays have been optimised with alumina ceramic and CoCr wear particles. These include simple vesicle leakage assays, tethered model membrane assays and more complex plasma membrane models containing proteins as well as phospholipids, to assess whether particles pass through cell membranes or cause damage by binding to the cell membrane. Taken together this suite of cellular assays will assess in detail the in-vitro biocompatibility of SiN particles in comparison to other bearing materials e.g. CoCr and alumina ceramics.

Method Development – Taper Function

This task describes the framework for the evaluation of corrosion and taper micromotion and damage in total hip replacements. In this document the process for evaluation of retrieved taper components is described and how the information from such tests is then used to inform the measurements made of micromotion in laboratory tests. An important part of this study is the assessment of the surface tribocorrosion/tribochemistry films and this deliverable describes the assessment of the physical and chemical nature of the retrieved and laboratory test samples. The deliverable also covers the development of protocols for the assessment of tribocorrosion in a fretting environment relevant to the taper interface. The integration of electrochemical measurements, the measurements of wear and surface chemistry is described. A number of explanted components were analysed on different scales from those related to TEM to the macroscopic where whole interfaces (male) were analysed.

The clinical issue with implant failure seems to be directly linked to the interfacial motion at the taper junctions. Hence, protocols for the in-vitro measurement of relative motion within the taper interface are an essential for understanding taper performance and reliability. With two components being in contact under loading, wear emerges and accelerates corrosion, ultimately causing the failure of the implant. Retrieval studies showed that spatial scales down to the microscale are to be considered, asking for test set-ups with high precision and sophisticated error analyses in combination with finite element models.

There is no consensus about the quantities of relative motion that are critical for the onset of corrosive processes of the involved material couplings. Retrieval studies showed the importance of local contact conditions at the interface of taper junction (including the microscopic motion), determining differences in wear properties around the taper interface. The protocol is suitable for the measurement of these relative motions within the taper junction on the microscale, enabling the evaluation of taper performance in-vitro in the process of optimizing taper junctions.

The Biotribocorrosion laboratory was prepared for delivery of the ProSim Universal simulator scheduled for late July 2015. This single station simulator is capable of full construct hip, knee and spinal articulation and will be fully instrumented for electrochemical monitoring techniques. The Prosim LifeLongJoints Adverse Wear Hip Simulator was designed to address shortfalls in current compliance wear testing standards of hip implants, whereas the Prosim LifeLongJoints Universal Joint Simulator was designed as a research tool to get a more complete understanding of the joints themselves specifically the tribocorrosive properties under a range of conditions. The simulator was delivered in 2015 and matched the specification set out to SIMSOL.

Simulator testing

This task outlines describes the assessment of coated clinical hip replacement components in full hip joint simulators in order to assess the tribological performance of various SixNy coating processes through development. Two bearing systems were considered for the application of a thin-film protective SixNy coating; namely cobalt-chromium molybdenum (CoCrMo) metal-on-metal (MoM) bearings with the coating applied to both surfaces and metal-on-polymer (MoP) bearings with the coating applied to the CoCrMo metal femoral head.

As part of Deliverable 2.4 novel methods of simulation were developed including adverse loading and actual patient gait profiles to advance functional testing of hip replacement components. In collaboration with the Leeds Teaching Hospital Trust (LTHT, UK) and Anybody Tech (ABT) patient gait profiles were developed and converted in order to run on the advanced Full-ISO Electromechanical LifeLongJoints simulators. The first conditions investigated were a Low (< 25) and High (> 30) BMI patient walking profile. Whereas earlier coatings were training samples and did not always conform to the target profile final coatings seemed promising and the coatings will undergo further development beyond the life of LifeLongJoints by the consortium partners.

Key Corrosion Results

The purpose of this stage of assessment was to compare the fretting corrosion current generated at the taper interfaces of a metal – metal couples. In one case, the trunnion is coated and in the other, the trunnion is uncoated thus the effectiveness of the coating at the taper interface is assessed. To achieve this, the CoCrMo femoral head is assembled against a coated/uncoated metallic substrate of CoCrMo and Ti6Al4V. Fretting current is thereby monitored through in-situ electrochemical set-up during cyclic fatigue loading.

Prior to fatigue loading, the OCP is monitored for a few thousand seconds. An anodic potential is applied and allowed to settle a few thousand seconds for the exponential decay of current to drop close enough to zero Amps. A fatigue loading is applied according to a given protocol at a frequency of 1 Hz.

The taper interfaces of coated CoCrMo and Ti6Al4V samples had about 50% less fretting corrosion current relative to an uncoated taper interface of CoCrMo - CoCrMo. This was the case for all loading profiles except for 1kN cyclic load where no fretting current was measured for all three material combinations.

No significant differences in the pull-off forces at the modular taper interfaces of coated and uncoated trunnion after a total of 2 hours cyclic loading for design A (p>0.999; see Figure 1) and design B (Ti: p=0.086; CoCr: p=0.163) was observed.

No significant differences in the pull-off forces at the modular taper interfaces of coated and uncoated trunnion after a total of 24 hours cyclic loading for design B (p=0.795; see Figure 2) was exhibited. Similar results were found for group A (p>0.999). However, CoCr trunnions of design A showed significantly higher pull-off forces for uncoated samples (p<0.001). Higher number of loading cycles reduced the standard error of all specimen groups and led to similar pull-off forces – except CoCr design A, uncoated. This might be caused by completed head seating of all junctions after a higher number of loading cycles.

In this deliverable results have been presented that have shown how the coating in each phase (preliminary and optimised) can offer potential benefits in the modular taper junction. This has implications for the performance of this interface; one that has been causing great clinical concerns over the last few years. The main benefits accrued by the application of the coating are (i) reduction in the production of wear debris in this interface and (ii) the reduction of metal ions from the taper interface. Both have great practical significance for the optimisation of the THR system when using Metal-on-ceramic, metal-on-polymer or ceramic-on-ceramic components.

Biocompatibility of SiN

Deliverable D2.6 describes the assessment of the biocompatibility of silicon nitride wear particles, both model particles and those generated from SiN coated prostheses. The SiN particles were compared to biomaterials widely used in total joint replacement prostheses, e.g. cobalt chromium and titanium alloys, which are also used as substrates for coated prostheses and ultrahigh molecular weight polyethylene (UHMWPE) used as a counterface to coated and uncoated metal alloys. A tiered toolkit of biological assays to determine the biological impact of wear particles was developed and disseminated through consensus agreement in a CEN Workshop Agreement (CWA 17252-2; see Deliverable 6.6 CEN Standards Workshop Reports). The toolkit included assays for wear particle cytotoxicity, inflammatory cytokine release, oxidative stress and DNA damage.

Irrespective of the particle size, silicon nitride model particles and coating particles did not cause any adverse responses, whereas cobalt-chromium wear particles caused donor-dependent cytotoxicity, TNF-α cytokine release, oxidative stress and, DNA damage in PBMNCs after 24 h. Despite similar size and morphology, silicon dioxide nanoparticles caused the release of significantly higher levels of TNF-α compared to silicon nitride nanoparticles, suggesting that surface composition influences the inflammatory response in PBMNCs. Ti-6Al-4V wear particles also released significantly elevated levels of TNF-α cytokine in one of the donors. This study demonstrates that silicon nitride is an attractive orthopaedic biomaterial due to its minimal biological impact on human PBMNCs.

Irrespective of the phase structure, silicon nitride particles were non-cytotoxic and did not cause release of TNF-α. Moreover, no significant production of reactive oxidative species was observed compared to the cells only negative control. Conversely, positive control cobalt chromium wear particles induced cytotoxicity and oxidative stress in the PBMNCs from at least one of the human donors after 24 h. The results from this study indicate that silicon nitride has low biological impact in the different phase structures tested, increasing current understanding of this potential biomaterial for healthcare applications.

Whether applied as a coating for hard-on-hard bearings (SiN vs SiN producing SiN particles) or hard-on-soft bearings (SiN on UHMWPE producing UHMWPE particles), the presence of the SiN did not cause adverse responses. In fact, the opposite was observed in cells challenged with UHMWPE particles generated against SiN coated plates, where inflammatory cytokine release and oxidative stress were significantly reduced compared to UHMWPE particles generated against CoCr alloy plates.

All the results obtained in this project indicate that biologically SiN is biocompatible and has low biological impact regardless of the particle size, phase or volume dose the cells are challenged with.

3. WP3: Computational Modelling and Simulation of Hip Joint Mechanics and Wear

WP3 had 6 objectives:

O3.1 - Development of a prototype whole-body-scale simulation model for determination of loading cases of initial adverse loading scenarios.
O3.2 - Fluoroscopy-based analysis of gait in sample population undertaken.
O3.3 - Validation of a body-scale hip implant model using data gained from 3.2.
O3.4 - Population simulations for adverse loading scenario determination using validated model from D3.3 undertaken.
O3.5 - Development and validation of surface tribology model against simulator data from WP2.
O3.6 - Computational prediction of implant wear using a multifaceted approach across the pertinent parameter space undertaken.

Each objective was linked to a deliverable as is the case in the other modules. All deliverables were completed.

Task 3.1 - Prototype of whole-body-scale simulation package for determination of loading cases of initial adverse loading scenarios.

Work on this task culminated in the submission of D3.1 and therefore the completion of a prototype of the whole-body-scale simulation package built on AnyBody technology. The model is an extension of the TLEM model, the previous state-of-the-art for lower extremity models. The prototype fulfilled all important goals defined for the model, including scalability, adaptability for the simulation of a variety of activities of daily living, a software interface to allow the direct importation and use of laboratory motion capture data to drive the model and, finally, the integration of a hip implant model into the whole-body simulation model.

Task 3.2 - Validation of whole body level model.

Model improvement and iterative validation continued throughout the project, beyond the deliverable date of M36, to ensure that new findings were implemented into improving the quality of the simulation model. An initial series of video fluoroscopy gait studies was performed and reported on at M36 (D3.2). These described treadmill gait in a small population sample and highlighted the patient-specific nature of hip kinematics, while also providing image data for the development of new 2D-3D image registration methods. The overall accuracy of the musculoskeletal model was demonstrated at M36 through the comparison of predicted ground reaction forces to measured values and the completion of detailed sensitivity studies to highlight factors with the greatest influence on model predictions (D3.3).

To ensure standardised use of the model for future research, an automated generation of model validation documentation was implemented into an HTML-based dynamic document presenting the results of the LifeLongJoints work.

An important outcome of the project was the direct comparison of the model predictions to in-vivo measures of hip joint force from the "Orthoload" instrumented prosthesis dataset. These validation trials highlighted shortcomings in the anatomical representation of muscle lines of action and wrapping behaviour in the prototype model, which were corrected and resulted in a substantially improved joint force prediction accuracy, with errors less than 0.25x bodyweight.

In a final series of video fluoroscopy trials, 15 additional patients were measured with a sophisticated 3D-tracking radiographic imaging system. This system was updated and modified during LifeLongJoints to allow hip joint imaging during free walking, stair descent, standing up and putting on a sock, while ensuring a minimum radiation exposure for the subject. The results of these trials provided quantitative data on real-world kinematic patterns and extents, as well as quantifying the under-prediction inherent in camera-based motion capture systems due to skin-motion.

Task 3.3 - Activities of daily living model library.

The essential elements of this task were completed, with a shift in focus from simulated dynamic motion patterns driving the musculoskeletal model, or even forward-dynamic muscle activation of the model, to the direct use of the kinematic datasets from the large LTHT cohort. Kinematic and kinetic data were measured in a large patient population for a variety of activities of daily living, and methods were developed and implemented for efficient batch processing of the motion-capture data for direct implementation in the musculoskeletal models.

The activities of daily living (ADL) library is therefore predominantly based on LTHT data, providing both single-subject and population averages for inclusion in the model repository. The kinematic and kinetic data itself will be provided as an open data asset with a unique DOI to allow referencing. Development of dynamic ADL models has proven to be a significantly larger challenge than expected, however good results were demonstrated in e.g. a sit-to-stand model that was improved through several iterations. Both the LTHT-based ADL motion trials and the predictive ADL models were reported on in D3.4.

Task 3.4 - Population simulations for load case determination [M12-M42].

This task was very closely linked to the progress in Task 3.2 and 3.3. The use of patient-derived ADL models, based on the LTHT dataset, for T3.4 and the related D3.4 was pursued as the most promising path to provide realistic, biofidelic predictions of hip joint loading across a relevant population. Representative population data have been delivered, with the definition of hip joint forces and kinematics across the large patient population for activities such as gait, lunge, sitting etc. The full datasets and their average profiles were described in D3.4.

A key feature of the population simulations was the ability to stratify the patient groups, and therefore the predicted values for hip contact force, according to several key classifications of the sample population. Patients were stratified according to body mass index, age and functionality (determined by average gait speed). Important differences in joint loading were found between sub-groups. In this work, we have outlined also the translation of these population simulations into representative "daily loading scenarios", comprising mixed activities of varying duration and magnitude, for use in both T3.6 and WP2 for the more realistic prediction of implant wear.

Task 3.5 - Development and validation of surface tribology model against simulator data from WP2.

The developed model of elastohydrodynamic lubrication, including the role of non-Newtonian lubricants, has been further refined during LifeLongJoints and used to evaluate hypotheses about the development of fluid film thickness during joint articulation. The role of the shear thinning properties on the minimum film thickness was quantified and shown to potentially play a role in determining the level of wear predicted on the joint surface due to its role in determining the film thickness variation with time.

The joint-scale wear model, based on the underlying EHL simulation, has been used to evaluate the role of slightly non-spherical geometry (due to surface wear), which must be considered along with changes in the deformation of the bearing surface in response to the pressurisation of the bearing surface. The model was further developed to consider the response as fluid film thickness is depleted below 1 μm. Two approaches were compared, the first preventing fluid film depletion with load below a specific characteristic length, with the deficit in load maintained by solid contact. The second approach applied a model of mixed lubrication in wear, with a partitioning of the load from fluid to solid contact as the gap decreases below the characteristic surface roughness. The model predicted a relevant, non-linear wear rate and asymmetric wear on the two components, which matched physical simulator wear results.

Task 3.6 - Computational prediction of implant wear using implant scale FE models across the pertinent parameter space.

In Task 3.6 wear was assessed across the parametric space established in the preceding tasks of WP3, using a wear model that extended the capabilities of the surface tribology model reported in D3.5.

This improved model recognizes that at the microscale, both the head and the cup are rough and the lubricant squeezes within the mating rough surfaces, enabling a mixed lubricated contact. Asperity-to-asperity contact leads to accelerated wear and local material removal. The developed wear model considers a mixed lubrication including the effects of roughness and elastic deformation of the polymeric cup surface, using a probabilistic distribution function to describe surface roughness across the whole implant. This mathematical framework investigates how the wear is estimated in a mixed lubricated contact, how the wear updates the roughness and how the wear is influenced by adverse load and motion patterns. The initial model was compared with the ISO standard gait cycle, followed by comparing with the adverse load and motion obtained from the LTHT trials and their corresponding musculoskeletal models. The numerical results on wear of the PE cup demonstrates a clear ‘run-in period’ before a lower steady wear rate is attained, mimicking physical wear simulation results.

Highlights of Most Significant Results

LTHT has delivered an unprecedented patient dataset of kinematics and kinetics. The dataset has proven to be a good foundation for the validation of the whole-body modelling framework, for the definition of severe loading scenarios for physical wear simulators, and for a comprehensive understanding of the role of critical patient-specific parameters on joint loading. The dataset is unique in the world for both the size of the measured group (>150 patients) and the broad assortment of activities of daily living that were measured.

Simulated hip contact forces (HCF) have been comprehensively validated against measured forces from instrumented hip implants in the Orthoload dataset. The simulated data was based on the measured patient activities in the LTHT dataset. Results showed good agreement between in-silico simulations and experimental data following extensive improvements to the model muscle description. The resulting improved and validated model is part of the public AnyBody Model repository.

Methods for motion capture-based musculoskeletal simulation models have been substantially extended. The AnyBody musculoskeletal modelling framework has been improved significantly, including GRF prediction, during the LifeLongJoints project. A paper on validation of GRF prediction for demanding sports related activities was published, demonstrating the potential for driving the models with kinematic data alone. Furthermore, batch processing methods developed during LifeLongJoints allowed the efficient processing of the large-scale LTHT motion trials, and this represents a significant advance in musculoskeletal simulation.

Dynamic ADL models have been demonstrated. The ability to drive the musculoskeletal model by parametric descriptions of motion was proven, i.e. without existing motion-capture data. A sit-to-stand (STS) ADL model prototype was developed by ABT using optimal control (OC) methods and iteratively improved for enhanced balance and realism.

The influence of clinical factors (e.g. implant placement, muscle asymmetry, anterior vs. posterior approach) on HCF has been explored. Patient data gathered at the KWS and LTHT were directly implemented into simulation models. Only a modest effect of muscle asymmetry was found, however an important influence of implant placement, i.e. cup medialisation, on HCF was found, with relevance for future wear simulations.

Quantitative analysis of video fluoroscopy gait trials has revealed a large degree of heterogeneity in the joint kinematics of individual arthroplasty patients. Individual "outliers" may represent demanding cases for implant loading and wear. Unique 2D-3D registration methods have been developed for solving the indeterminacy of acetabular cup position in the radiographic image (rotationally symmetric structure) by using pelvic landmarks. Direct comparison of synchronized camera-based motion capture data with fluoroscopy data has shown a relevant under-prediction of joint motion by motion-capture, with important implications for the definition of wear testing protocols.

The EHL lubrication and wear model has been used to simulate the wear over the gait cycle employed in hip simulator tests. The wear results qualitatively predicted the typical non-linear wear curve obtained from experimental hip simulator tests, with an initial ‘running-in period’ before a lower wear rate is reached. The heterogeneous wear scar can be simulated on both the acetabular cup and femoral head bearing surfaces. The lubrication and wear models have been extended to include a description of the surface roughness, and the modification of roughness through wear. LTHT-derived daily loading protocols have been successfully run in the wear simulations.

4. WP4 - Device Prototyping and Manufacturing Scale-up of Silicon Nitride Coatings

Specific Objectives:

O4.1 - Develop a technical specification of industrial scale equipment.
O4.2 - Construct an industrial size PVD-HiPIMS coating equipment built according to the technical specification developed in Task 4.1.
O4.3 - Establishment of coating processes and coating distribution for industrial size equipment.
O4.4 - Coating of functional prototypes for hard-on-hard bearings and tapers, including preliminary coating characterization.
O4.5 - Installation qualification of production scale coating machine.
O4.6 - Medical devices coated with silicon nitride coatings, full batch, delivered for assessment in WP2 and detailed coating characterization, evaluation and testing within the current WP.
O4.7 - Operational and Performance qualifications of silicon nitride coating in production scale equipment.
O4.8 - Preparation of final report on opportunities and eventual limiting boundaries of silicon nitride based coatings produced at industrial scale.


The history of Coatings on Orthopaedic Applications

The Gen I TiN coating industrialized by Ionbond

The development cycle of a new coating and new coating technologies typically take place over a period of about 10 years. Coatings such as Titanium Nitride (TiN) were developed based on PVD cathodic arc evaporation in the 1980s and deposited over tools mainly for cutting and forming applications. It was only in the 1990s that TiN coatings and coating application-processes were developed and sufficiently controlled to be applied onto orthopaedic implants. Ionbond was a pioneer in the application and commercialization of TiN coated implants in the market during the 1990s and following decades. The TiN coating material had first to be tested for its biocompatibility in vivo with very long wear tests - up to 48m cycles (figures 2 and 3). These tests were carried out to give confidence to surgeons to use these coated implants in patients in which other implants were rejected. The first patient applications showed success and motivated orthopaedic companies to validate the TiN solution as an option within the portfolio, such as the DepuySynthes TiNi LCS knee.

Equipment developments into Generation II with smoother and more uniform coatings

The use of planar rectangular targets on PVD arc evaporation systems instead of the round/random arc systems allowed better arc steering and therefore less droplet emission. This led to smoother, more uniform coating thickness distribution over height of the coating chamber. Also the introduction of steered arc evaporation “with several coils for magnetic field steering” (figures 4 and 5) allowed smoother coatings to be deposited due to evaporation over a wider surface of the target preventing the formation of large droplets leading to less coating defects. For these reasons, the Medthin 01 TiN Generation II is a better coating when compared with the Gen I TiN coating. In addition, multilayers from this generation of coatings, such as the AS coating from Aesculap, have proved themselves in the market to be a smart solution to increase wear resistance, and reduce ion release in CoCrMo knee implant systems.

Generation III Coatings - to support high volumes of coated implants

Industrial Scale SiN

In the frame of the LifeLongJoints project (LLJ), Ionbond delivered to the LLJ consortium several packages of development work, which was needed to adapt parameters to large scale coaters at Ionbond . A systematic evaluation of possible root causes of poor mechanical properties of the first work “package A” - SiN coatings was done and several work packages A, B, C, D, E were done to develop and optimize the industrial process. The first coatings from package A were not responding to the expected level of tribological performance due to low hardness and poor grain-structural density. Five packages of work, with over 100 coating runs were performed to achieve the final industrial SiN coating.

SiN FINAL - a dense coating

After 2.5 years of research we were pleased to see promising coating parameters with some modifications of the parameters, especially on the collection of ions from the emitting Si targets using a more significant bias voltage.

Opportunities with HIPIMS coating technologies

In a continuous effort to improve deposition technology and coatings, the LifeLongJoints project offered an opportunity for Ionbond to prepare the next generation of coatings and High Power Impulse Magnetron Sputtering (HIPIMS) technologies, and to offer these coating technologies to the orthopaedic industry. With the use of HIPIMS one can obtain a coating that is smooth but is also dense and well adhered to the substrate. The HIPIMS technology uses high energy peaks in order to increase ionization to levels that were observed before only by arc evaporation techniques. HIPIMS gives the possibility to achieve nearly pin hole free coatings and therefore significantly improves ion release reduction as well as wear protection of implant bearings of coating implants in contact with UHMWPE.

Silicon Nitride coating deposited by High Power Impulse Magnetron Sputtering shows low roughness and less pin holes compared to coatings deposited with other older generation PVD technologies, such as Gen I and Gen II coatings. The microstructure of the SiN film is dense and there is no crystalline order, neither long nor short order. In a cross section the FINAL SiN, “MedthinTM 53 SiN” we can see that the coating is a good candidate for application on implant bearings to reduce wear and ion release from CoCrMo or other metallic alloys. Silicon Nitride coating is a solution to address the needs of metal sensitive patients.

Summary of properties of the SiN coating:

• Dense, amorphous structure
• Hardness >20GPa
• Roughness, Ra<30nm as-coated
• Scratch resistance Lc3>40N
• Rockwell indentation Class 1
• Virtually no pin holes in the coating

The future

The Generation III SiN coatings coated with HIPIMS technology are good candidates for use on orthopedic implants and implantable devices due to their smoothness, high hardness and chemical controlled stability. Any SiN coating debris have proven to be dissolvable in serum, which is a positive property should any debris be generated during the expected extended lifetime of the SiN coated joints implanted in the human body.


5. WP5: Assessment of Silicon Nitride Coating Performance In-vivo

In this work package relevant in-vivo animal models were developed and also experiments conducted to assess: i) biocompatibility, resorption of generated wear particles with synovial joints, ii) overall performance of wear of the new implants in rabbits and a large animal model which allows longer-term assessment of implant performance, iii) the cellular response of the local tissue in a diarthroidal joint (bone, synovial membrane, periarticular structure).
Specific objectives of WP5 were:
O5.1 – Design of a new model for a stifle joint prosthesis in rabbits
O5.2 – Biocompatibility testing of wear particles in rats
O5.3 – Design of a new model for a partial stifle joint prosthesis in sheep
O5.4 – Rabbit experiments with stifle prosthesis for biocompatibility and wear assessment undertaken.
O5.5 – Experiments with sheep to test long-term wear of partial prostheses in stifle joint undertaken.

Each year progress towards the milestones and deliverables were made according to plan. The customized design of the new model of a stifle joint prosthesis and the surgical technique in rabbits (WP5.1.) as well as the design of the new model for a partial stifle joint prostheses in sheep (WP.5.3) were achieved together with the partners of the ETHZ. The biocompatibility testing in rats (WP5.2) was performed in collaboration with the partners from the UNIVLEEDS, whose expertise and new methods to isolate wear particles from living tissue served well to determine the biological reaction to SiN particles injected into the stifle joint. Their support was also invaluable for the experiments in rabbits (WP5.4) where short term evaluation of non-coated and with SiN coated prostheses were tested in rabbits. These in-vivo experiments were delayed time wise due to the delay in production of the appropriate prostheses and fabricating the ideal SiN coating for the chosen metals, titanium and cobalt chrome. Problems in adhesion of the coating warranted additional time. The in-vivo experiments in rabbits were completed, although the histological evaluation is still ongoing and will be completed in the autumn of 2019. Last, WP5.5 dealing with the in-vivo experiments with partial prostheses in sheep had to be cancelled mainly due to ethical reasons. At the time when the experiments should have been performed, the appropriate SiN was not yet available and after conducting the short term experiments in rabbits (WP5.4) with short comings of the SiN coating, the consortium decided that there was no justification to use living animals for the long term experiments before the ideal coating could not be found. Specific high lights and achievements are specified below.

The in-vivo experiments were all conducted according to the Swiss laws of animal protection and welfare (TSchG 455) and were authorized through the local cantonal authorities.

Year 1 - The first year was mainly used to establish methodology (UNIVLEEDS, UZH), design the prosthesis according to real CTs of rabbits (ETHZ,UZH), planning the animal experiments in rats and rabbits, preparing documents and getting ready for the GLP approved study (UZH).

Highlights of the first year were the:

• Establishment of the surgical technique for placement of prosthesis
• First draft for prosthesis design
• High resolution FEG-SEM imaging of model SiN particles
• Understanding of aggregation behaviour of SiN particles
• Generation of control particles for in-vivo studies in progress
• Establishment of histological procedures for visualization of SiN particles in tissue by light microscopy in place.
• Rat experiments under planning with study plan and SOPs under development including animal permission.
• GLP accreditation of MSRU facility was in its final phase.

Year 2 - In the second year all work of year 1 was continued and additionally the design of the partial stifle prosthesis for sheep was started, again with the help of real CT and cadaver studies (ETHZ, UZH). Meanwhile UNIVLEEDS prepared the SiN particles with full characterization. In addition, the isolation method of particles was further improved, such that the efficacy if particle isolation could be increased 20-fold compared to reported methods in the literature. First prototypes of rabbit prosthesis were produced with 3D-printing technology. However, this technology did not achieve the desired surface roughness that allowed coating with SiN with the appropriate adhesive properties. Several attempts were made to adapt the surface, but results were not satisfactory. Besides establishing isolation methods, the UNIVLEEDS also prepared and characterized the SiN particles for the rat experiments, where SiN particles were injected intra-articularly into the stifle joints (UZH). Commercially available model SiN particles of ca. 50nm were used, since tribology tests on with SiN coated disks did not generate enough particles which were required for the rat experiments. The animal experiments were started with reference items, titanium and cobalt chrome as controls. Two survival time points of rats were chosen to establish biocompatibility at 2 and 7 days after injection. The low and high dosages of nanoparticles injected were calculated according to the results obtained in the in-vitro experiments of the partners at the UNIVLEEDS.

Highlights of the second year were the:

• Planning of design for the sheep partial prosthesis of the medial femoral condyle
• Finalizing of rabbit prosthesis design / starting production with 3D printer technology
• Preparation and characterisation of SiN particles for rat study
• First rat experiments conducted with reference item

Year 3 - The consortium decided to expand and adapt the rabbit experiment design. New, uncoated CoCr, SiN coated CoCr and SiN-coated Ti-6Al-4V prostheses were planned to have a standard control and two type of metals to be used with SiN coating. The production of the rabbit prostheses still caused problems in the third year. The surface roughness was not ideal and pits were noticed in the sandblasted and polished 3D printed surfaces of the titanium models (ETHZ). First attempts with SiN coatings failed due to the short-comings in the metal surface. Conventional 5-axis CNC machining at the ETH Zurich showed better results and therefore, finally the prosthesis were produced in a specialized medical device company in Switzerland (Jossi Orthopaedics) using conventional machining technology. Furthermore, the surgical technique was refined and special equipment and instrumentation was produced for the in-vivo implantation of prostheses into the rabbits.

The design of the partial stifle prostheses for long term experiments in sheep was further pursued and the surgical technique adapted. Due to the narrow joint situation in sheep, the instrumentation and techniques used in humans could not be applied. New instruments were developed. Multiple cadaver tests were conducted with the partners of the ETHZ:

The histological evaluation of first rat experiments confirmed initial results of good biocompatibility of SiN particles injected into the stifle joints. The inflammatory response to particle injection was minimal and much less with SiN compared to CoCr wear particles (UZH). Customized score systems were developed to evaluate the tissue reaction of cartilage, synovial membranes, lymph nodes, liver and spleen.

Particles could be extracted and quantified from entire stifle joints of rats that were sent to the partners at the UNIVLEEDS.

Highlights of the third year were the:

• New production of sandblasted and polished prototypes of rabbit prostheses and first coating experiments
• New design concept for a partial stifle joint prosthesis in sheep and preliminary surgical trials in sheep cadavers.
• Completion of all rat experiments in-vivo.
• Preparation of histology using decalcified stifle joints of rats embedded in paraffin and stained with HE.
• First results that showed high biocompatibility of SiN particles compared to controls.
Year 4 - In the 4rth year the problems with manufacturing the rabbit prosthesis could be finally solved. Prostheses were produced out of titanium and CoCr (ETHZ, UZH). Also the coating process could be completed at our industrial partners from Ionbond. Final instruments were produced (cutting guides, templates, screws, etc.) and surgical technique could be standardized with repeated good and reproducible results. A hand surgeon (Professor Maurizio Calcagni, UZH) became part of the team. His expertise greatly improved the outcome. The GLP study plan was finalized and signed.
The evaluation of the histology slides (>2000sections!) of the rat experiments was very complex, time consuming and quite challenging for interpretation. In summary, it can be confirmed that the SiN particles were detected within the joint structures, also the effluent lymph nodes, but not in the liver or the spleen. Reactions to the injection of wear particles of all groups were dose-dependent (low /high dose). Within the joint structures, the synovial membrane showed an immediate response to the injection SiN particles after 2 days, which subsided fast and was considerably down regulated at 7 days already. In contrast the control groups showed less inflammatory responses at 2 days but steadily increased thereafter until day 7. Evaluation of cartilage showed a significant increase in remodelling of the tide mark in response to wear particle injection but no significant changes in the hyaline cartilage structure.

Optimization of the design concept for the partial stifle joint prosthesis for sheep was pursued and was almost complete. Customized instruments were and still are designed for more accurate placement. An orthopaedic surgeon. PD Dr. Christoph Erggelet, was consulted for optimization of the partial prosthesis. As a consequence improved instruments were designed. However, final production of the partial prosthesis was withheld since the consortium decided to wait with the in-vivo experiments with sheep until the results of the rabbit study (WP3) were available.
Highlights of the 4rth year were that the:

- GLP study plan for rabbit experiments was finalized and signed
- Evaluation of rat experiments was concluded.
- Results of the rat experiments confirmed the initial impression that SiN are biocompatible and have a down-regulating effect on inflammatory reactions subsequent to surgery
- The doctorate thesis of med.vet. Florian Hipp was accepted.
Year 5 - In year 5 finally all rabbit experiments could be conducted (UZH, ETHZ, UNIVLEEDS). The in-live phase of the three groups (plain cobalt chrome prostheses as controls, SiN coated cobalt chrome and titanium implants as test items) could be completed. A total of 27 rabbits were operated. In life documentation with radiographs and clinical examinations, as well as sacrifice of all rabbits was completed. Particle isolation and characterization out of the 3x3 whole stifle joints could also be completed. Histology of all other 18 rabbit joints is still ongoing at the UZH and will be completed after termination of the project. The reason for this delay is due to the fact, that the coating technology was not ready in time. Therefore, the animal experiments could only be started in July 2017 (M49) and surgeries completed in December 2017 (M56).

Nevertheless, all surgeries could be completed and went well. Rabbits were ambulating directly after recovery and throughout the period. Radiographs proved good fit of the prostheses components. Luxation of the joint occurred only in one rabbit. While the control prostheses showed macroscopically no sign of wear or wear particle formation, instead the SiN coated prostheses revealed considerable wear at the weight bearing area of the femoral and tibial components of the prostheses. The joint cavity was filled with wear particles such that serious black discoloration could be noticed already macroscopically from outside the joint capsule. Wear was more pronounced in the coated titanium prostheses compared to the cobalt chrome. Thickening and fibrosis of the joint capsule with limitation of joint movement was the result clinically. Histological evaluation of the first specimens (not all have been completed yet), however, demonstrated that despite the excess wear particle formation, tissue reaction to the abundant SiN particles was relatively mild. No excessive inflammatory cellular reaction could be observed and the prostheses were still fixed in place.

With these results of the short term experiments in rabbits, the consortium decided not to continue with the animal experiments in sheep, mainly for ethical reasons. It could not be justified to use living animals with a coating that did not adhere to the metal implant sufficiently to withstand the wear of only 3 months.
Highlights of the fifth year were the:

• Completion of implantation of rabbit prosthesis and in-live phase of rabbits
• The good function of the rabbits prosthesis design
• Standardized and very sensitive method of isolation of particles from synovial joints with implants in situ
Conclusion for WP5

In summary, the in-vivo experiments with rabbits have shown clinically and radiologically that the design of the stifle joint prosthesis was clinically successful. It is the first truly customized prosthesis created for experiments in rabbits. Until now, only finger prosthesis of humans were used and described in the literature. Therefore, the new design is a real asset in the world of animal models for preclinical studies.
Nevertheless, although the design proved highly suitable, at this point it can be concluded that the SiN coating at the coating used in these in-vivo experiments were not safe for being used in metal to metal joint prosthesis. In the mean-time our partners of the LifeLongJoints have continued to improve the coating technology and were able to produce a more stable and homogenous coating. The consortium decided that although the LifeLongJoints project was officially terminated the partners would raise new money to continue the collaboration and come to a functional coating. In addition, the metal-to-metal prosthesis has been mostly abandoned during the duration of the project, and therefore, research with the improved SiN coating should be expanded to prostheses containing also polyethylene components. Last but not least, the anti-inflammatory effect of SiN on tissue reactions should be further investigated and used to the advantage of anti-corrosive characteristics on the metal implant itself.
The partners form Switzerland (ETHZ, Ionbond, UZH) will submit a new grant proposal to the Innosuisse grant agency to finalize the SiN coating for clinical use.

6. WP6 - Medical Device Regulation, Exploitation and Dissemination

The objective of Work Package 6 ‘Medical Device Regulation, Exploitation and Dissemination’ was to ensure the timely organisation and execution of those activities necessary to ensure the results of the project are presented in the best possible manner for exploitation and use. This entailed ensuring dissemination of results to stakeholders influential in winning clinical acceptance and ensuring the necessary groundwork for product development is addressed, including addressing issues relating to regulatory approval as well as attending to issues regarding exploitation by individual partners.

WP 6 activities are discussed in the exploitation section of the Final Report.
Potential Impact:
Exploitation

Five of the fifteen LifeLongJoints partners are commercially orientated organisations with an interest in exploiting results from LifeLongJoints for product development. This includes two SMEs. The WP6 Lead Partner, Tutech, worked with these organisations to oversee delivery of results in a form useful for exploitation. These are summarised below:

Result / Partners involved in developing knowledge base / Main prospective commercialisation partner(s)
New coating / LiU, Ib, UU, UZH, UNIVLEEDS / Ib with PB and AAG
Enhanced software for simulation / ETHZ, LTHT, KWS, ABT UNIVLEEDS / ABT
Hardware simulation/testing technology / UNIVLEEDS, TUHH, LTHT, KWS, SimSol / SimSol
Enhanced testing framework / UNIVLEEDS, TUHH, ETHZ, ABT, LTHT / SimSol, PB/AAG, ABT
Wider community - standards development / Enhanced cytotoxicity testing / UNIVLEEDS, UZH

In the Description of Work five main results were foreseen as having commercial exploitation potential – a new coating; enhanced software for biomechanical simulation; Hardware simulation/testing technology; enhanced testing framework and enhanced cytotoxicity testing. These were largely achieved though the project did not achieve within the timeframe of the contract a fully functional silicon nitride coating. LifeLongJoints has, however, produced a very substantial body of knowledge around the performance of silicon nitride coatings and their industrial production. It was the transfer of processes and parameters from lab to industrial production that proved more demanding than envisaged. Ionbond, foreseen as the main commercialisation partner for the coating and coating process technology, remains committed to the development of smooth coatings and expects to achieve a commercially usefully result in about 3 years after completion of the grant. The market demand remains

The most important areas of use for smooth silicon nitride-based coatings are mainly load bearing articulating joint surfaces. The specific advantages of “third generation” hard coatings - high hardness and wear resistance, yet so far unrivalled anti-friction properties – makes them appear one of the next major steps forward in development of artificial joint prostheses. A current preoccupation in the market is also the taper connection of hip implants as these are prone to steady failure. Coating a metallic male taper with silicon nitride addresses this issue by lowering the fretting current compared to a standard uncoated connection. LifeLongJoints has achieved promising results regarding the use of the coating on tapers that might enable the design and manufacturing of modular load bearing implants with significantly improved juncture which increases lifetime of the whole prosthesis.

LifeLongJoints has made considerable contribution to enhancing the state-of-the-art in the area of in-silico biomechanical simulation – an area of work regarded by the surgical members of the External Expert Advisory Board (EEAB) as being of considerable interest. The research work on biomechanics from ETH, tribological wear from Leeds and Imperial together with access to patients willing to help provide motion data at LTHT and KWS has provided the means for the SME simulation software specialist ABT to further develop their software and enhance the state-of-the-art in in-silico testing.

LifeLongJoints has provided SME partner with the opportunity to advance the state of its simulator technology to the mechanical limits of what is achievable (controlling all six axes of motion) through the development of a distributed control system which is now being used as the foundation for future generations of simulators, allowing a greater focus on in-silico manipulation of the axes to closer match in-vivo dynamics. SimSol forecasts sales of over £1m - £2.5m for simulators developed using results from the LifeLongJoints project. The large-scale, stratified data accrued from the clinical motion capture and subsequent gait analysis has provided the opportunity to test under a range of conditions associated with activities of daily living. The real life patient data collected has thereby established as foundation to do more real world testing and give direction to a new ISO/ASTM testing standard contributing to enhanced testing framework.

The Body of Knowledge of the silicon nitride coating developed by the project has been collated into a deliverable entitled “Preliminary Medical Device Dossier” (MDD) (although it is not a MDD the strict sense of product development).

The dossier provides information pertaining to market requirements and market rationale for improved hip implant performance, giving the rationale for the specific solution chosen, a silicon nitride coating deposited by high power impulse magnetron sputtering (HiPIMS), the anticipated performance of products utilising this, and the standards that would apply to a successful product in order for it to be placed on the market. At commencement of the LifeLongJoints project, a specification was agreed for a series of coating parameters. The coating was deemed biocompatible and showed no cytotoxic or genotoxic responses compared to CoCr, in-vitro and in-vivo. Soluble particulates were demonstrated with a surface dissolution rate for the bulk material being dependent on the exact composition. Coating roughness and thickness matched the specification. Coated samples showed a much reduced ion release relative to uncoated CoCr, whilst scratch tests demonstrated values in excess of 30 N for Lc2. Wear resistance for hard on hard bearings was poor, whilst early samples failed through dissolution for metal on PE. Later samples showed promising wear results albeit for short term tests.

Contribution to standards

A key result of LifeLongJoints from the work on in-vitro simulation and biological assessment of wear conducted by the University of Leeds has been the development of novel methodology to isolate very low volumes of wear particles from simulator lubricants and tissues which is 100-fold more sensitive compared to current methods. The work has been presented for wider use through the publication of two CEN Workshop Agreements:
• CWA 17253-1 “Joint implants — Part 1: Novel methods for isolating wear particles from joint replacements and related devices”; and,
• CWA 17253-2 “Joint implants — Part 2: Tiered toolkit approach to evaluate the biological impact of wear particles from joint replacements and related devices”.

These Workshop Agreements are available from the CEN website: https://www.cencenelec.eu/standards/Sectors/healthcare/MedicalDevices/Pages/WS87.aspx.

Further exploitation of these results will be pursued through turning CWAs into EN or ISO standards. CWA 17253-1 could become part of ISO 17853:11 and CWA 17253-2 could become part of ISO 10993.

The results generated to date indicate that SiN particles are well tolerated by different cell types at a range of concentrations (from low to very high) and are biocompatible.

LifeLongJoints has amassed important real life patient data accrued from the clinical motion capture and subsequent gait analysis providing the opportunity to test under a range of conditions associated with activities of daily living. This work has established the foundation to do more real world testing and give direction to a new ISO/ASTM testing standard. This requires a 'buy in' from the ISO/ASTM Members that the current standards are inadequate and can be bettered and so is a slow process. However, through the work of LifeLongJoints, a validated musculoskeletal model has been developed through the collaboration between LTHT, ABT and ETHZ which can accurately predict joint contact forces (JCF’s), thereby better predict wear and show how improved testing standards can be achieved.

A conclusion of the project is that in-silico simulation methods are still quite far from being generally accepted by industry and regulatory organisations, possibly even further than before LifeLongJoints, due to the changed regulatory landscape since LifeLongJoints commenced. Manufacturers are now required to produce more regulatory documentation based on current testing standards. For in-silico approaches to be adopted more expertise needs to be established in both regulatory bodies and manufacturers. The results from LifeLongJoints support this by enhancing the uptake and greater acceptance of the value of in-silico developed adverse loading cases through the LifeLongJoints datasets and publication thereof. It is hoped that this will lead industrial early adopters to demonstrate the value of in-silico parameter/ population studies as a pre-step to dedicated physical testing. Acceptance of these steps could lead to development of standards for pure/partial in-silico testing product assurance. ABT is playing a pro-active role in promoting this.

Dissemination

Reaching out to a wider community of interested parties was an important task of LifeLongJoints. Dissemination of the project outcomes was driven via a number of complementary routes with the objective of reaching a wide range of researchers, industrialists, regulatory authorities and governmental organisations to maximise impact.

The target groups for dissemination were conceptually divided into the following groups:

• Inner Circle: Project Partners
LifeLongJoints was very much a multi-disciplinary project involving flow of knowledge from different disciplines, organisational forms and nations. There was continuous intensive dialogue between partners, work packages. The Partner Assembly too provided an important platform for sharing results and perspectives.
• Second Circle: Scientific, technical and clinical experts external to the project receiving regular information. This was done through the appointment of an External Expert Advisory Board (EEAB) to act as ‘critical friends’ (see below).
• Outer Circle: the wider scientific, technical and medical community who were reached through the website, events and extensive list of publications.

External Expert Advisory Board (EEAB)

At the commencement of the project an EEAB was appointed as a means to involve clinician and biomechanics experts external to the project from an early a stage to provide critical oversight of developments, and to establish a cohort of people who could act as independent disseminators of the outputs.

The Members of The EEAB were:

• Professor Maria Grazia Benedetti - Professor at the Ospedale Universitario Rizzoli (Istituto Ortopedico Rizzoli) in Bologna;
• Professor Vincent Gremeaux - Professor at the Centre Hospitalier Universitaire de Dijon (Pôle Rééducation – Réadaptation) in France;
• Professor Richard Hall - Professor at the University of Leeds;
• Professor Tom Joyce - Professor of Orthopaedic Engineering Mechanical and Systems Engineering, University of Newcastle;
• Professor Dr Frank Lampe - Professor at the Schön Klinik Hamburg Eilbek (Zentrum für Endoprothetik) in Germany; and,
• Professor Dr Catherine Van Der Straeten, MD, PhD Head of the Clinical Research and Innovation Institute and Network Ghent University Hospital, Ghent, Belgium and Honorary Senior Clinical Lecturer Imperial College London, UK.

The EEAB met once a year, from 2015 onwards, with members of the LifeLongJoints partners to receive presentations and discuss aspects of the project.

In addition to these meetings, with the support of Professor Van Der Straeten, clinicians were invited to attend a workshop at Imperial entitled The “Virtual Patient”. Professor Stephen Ferguson, ETH Zurich, Dr David Lunn, LTHT, and Dr Liaming Gao, Imperial, gave a special workshop to hear presentation about current advances in development of simulation systems relating to implants and the contribution to the field made by LifeLongJoints.

Publications

LifeLongJoints has contributed a substantial body of knowledge to the various fields addressed by the project. Some 90 scientific and technical presentations/publications have been made. These are listed on the project website and under 4.2 below. A number of early career researchers have received accolades for their work.

Outreach to the wider community

The project website www.LifeLongJoints.eu provide the vehicle for providing general information about the project with regular News items and videos.

Two events for patients were held: the first in Leeds in September 2015 when just under 100 hip replacement patients with friends and family gathered at Leeds University to hear how their contribution to the project has been used. A second event was held at the Schulthess Klinik in Zurich a year later with around 80 patients.

Video reports of these events are on the LifeLongJoints website at:
https://LifeLongJoints.eu/not-your-average-joint/
https://LifeLongJoints.eu/LifeLongJoints-meets-patients-in-zurich/

In addition, LifeLongJoints has been used as a training case in how to form multi-disciplinary partnerships to assure Impact of the work in very many training courses and presentations offered by Tutech reaching several hundreds of participants.

Video reports summarising the project

The following videos have been produced to summarise aspects of the project to a wider audience. They can be accessed from the project website, which will continue to be supported until at least 2020.
• Designing and testing implant coatings traces the process of developing a thin-film coating and presents the challenges and progress in scaling up the Silicon Nitride coating from the research lab to industrial level, the timescale for achieving a marketable coating, and the advantages HIPIMS technology offers in delivering smoother, more uniform coatings. It highlights the new testing methodologies that have been developed, including debris isolation techniques and cell response assays codified in CEN Workshop Agreements; mechanical simulators developed for the project that can mimic loading cycles for activities of daily living; methodologies to investigate what happens at the taper junction; and examining wear and corrosion as components of implant damage.
• Simulating and modelling hip joint mechanics and wear covers both computational and mechanical simulation of hip joint mechanics and wear. It shows computational modelling of hip joint loading, which incorporates gait analysis of hip replacement patients conducting activities of daily living into musculoskeletal simulation models. It also covers the incorporation of patient gait cycles into mechanical wear simulators, designed for the project, to capture motion within the implant and the resulting damage caused by both wear and corrosion.
• LifeLongJoints: anatomy of an EU research project explains the challenges the LifeLongJoints research project set out to address and hears from a range of partners about their contributions to the project and their insights and achievements in the past five years. Contributors also anticipate how medical device development and their own specialisms might progress in the next ten years.
• Wear prediction of total hip replacements: Dr Nilanjan Das Chakladar of the School of Mechanical Engineering in Leeds University’s Faculty of Engineering explains the computational simulation model he developed that can predict implant wear in a matter of hours. The model uses patient gait analysis data captured by Leeds Teaching Hospitals Trust.
• LifeLongJoints: a rare opportunity for early research shows young research graduates at Leeds University talk about their research and the unusual opportunities and challenges of being involved in a complex multi-national EU-funded project
• CEN workshop, Brussels, 26–28 September 2017 explains how LifeLongJoints has contributed to the enhancement of standards with the preparation of two CEN Workshop Agreements, voluntary standards applicable internationally. Professor Joanne Tipper and postdoctoral research fellow Dr Saurabh Lal from the University of Leeds talk about the two agreements, on novel methodology for wear particle isolation and on the biological impact of those particles in-vitro. The video also explains how Workshop Agreements enable research outputs to reach industry and includes contributions from industry representatives.

Evaluating the biological impact of wear particles: Professor Joanne Tipper and postdoctoral research fellow Dr Saurabh Lal talk about their research on isolating wear particles and evaluating their biological impact. They explain that their methodologies, which can be used for isolating very low volumes of wear debris from modern bearing materials and testing their biocompatibility using a range of assays, can also be used by other researchers on materials other than those studied in LifeLongJoints.

A series of short (<3 min) videos has been made to support the Commission’s action promoting Horizon 2020 results.
List of Websites:
LifeLongJoints Project Website: www.lifelongjoints.eu.

Contact Details

Coordinator

Professor Richard M Hall
Faculty of Engineering
University of Leeds
Leeds, LS2 9JT, UK

Telephone: +44 (0) 113 343 2132
Email: r.m.hall@leeds.ac.uk