Multifunctional bioresorbable biocompatible coatings with biofilm inhibition and optimal implant fixation LEMI Project Presentation

2 Content Aims Approach Problem statement & expected breakthroughs Envisaged radical innovations Scientific & technological objectives The Meddelcoat consortium Project structure & co-operation Project work plan Project milestones Expected impact Administrative information & contact

Project Presentation 3 Aims of the MEDDELCOAT project To develop the next generations of multifunctional bioactive biocompatible coatings with biofilm inhibition and optimal implant fixation, eliminating the currently experienced need for implant revisions due to implant loosening and infections.

Project Presentation 4 Approach of the MEDDELCOAT project Design and engineer the structure of the implant surface to optimise implant fixation by osteointegration, Promote osteointegration by the application of a bioactive top coating, Incorporate a biofilm formation inhibiting function into the coating. Combinatorial approach

Project Presentation 5 Problem statement & expected breakthroughs State-of- the-Art Problems How is this tackled in MEDDELCOAT Breakthroughs expected Bio- material Ti or Ti6Al4V substrates Limited biocompatibilit y of Ti6Al4V, to secure implant fixation until bone apposition Implant surface structuring or the application of a designed Ti mesh on the implant surface to secure implant fixation by osteointegration & development of new substrate materials New substrate materials, design coatings for fixation by osteointegration Bio- coatings Plasma sprayed Ti, HA or Ti + HA too low coating adhesion strength resulting in delamination, additional cost Design and application of new bioactive and resorbable top coatings with graded interfaces and tailored porosity on the structured implant surface. Tailored coatings with enhanced adhesion strength, mechanical fixation and an engineered stress distribution

Project Presentation 6 State-of-the- Art Problems How is this tackled in MEDDELCOAT Expected breakthroughs Biofilm inhibi- tion Limited to bone cement impregnated with antibiotics The use of bone cement and limited controlled release possibility Investigation of bacteria-material interactions. Selection, incorporation and evaluation of biofilm inhibitors. Biofilm inhibiting coatings or coatings with incorporated antimicrobial releasing carriers Ortho- peadic & dental Implants % revisions after years for orthopaedic implants 15 % revisions for dental implants after 5 years Aseptic loosening, implant dislocation, and bacterial infection Multifunctional bioresorbable coating with biofilm inhibition Prolonged implant life time (> 25 %), reduced need for revision surgery, reduced infection rate Problem statement & expected breakthroughs

Project Presentation 7 Envisaged radical innovations and major breakthroughs  Development of new substrate and coating materials with enhanced biocompatibility.  Development of radically new or improvement of existing coating techniques for the processing of bioactive and biocompatible coatings with a graded interface (adhesion strength) and tailored porosity (bone in-growth).  In-depth understanding of the implant substrate/coating/bone interfacial structure, the design, engineering and control for optimal implant fixation.  Novel knowledge on interactions between new coating materials and bacteria and effective biofilm avoidance/elimination routes  Evaluation of new biofilm inhibiting substances  A formulation for the incorporation of anti-infective substances into the coating

Project Presentation 8 Scientific & technological objectives NoDescription O1 The design and manufacturing of state-of-the-art dental, shoulder (glenoid and humeral bodies) and hip (stem and acetabular cup) implants suitable for the envisaged coating procedures. New substrates, such as nanostructured titanium-based alloys, will be developed and evaluated, aiming at a better biocompatibility compared to standard Ti6Al4V. The targeted E-modulus and fatigue strength of the new substrate material are respectively GPa and 550 MPa. O2 The development of bioactive glass (BAG), calcium phosphate and titania based precursors or powders for the processing of new bioactive coatings. The long-term fixation mechanism for the implant will be established by surface structuring or the deposition of porous Ti as an intermediate coating. O3 Define guidelines for the microstructural, compositional, morphological and mechanical requirements for bioactive coatings with improved mechanical fixation (static coating adhesion strength > 40 MPa) and biofilm inhibiting functionality. Definition of the selection criteria for the coating/substrate systems to be tested in vivo. O4 To investigate the possibility to use state-of-the-art techniques such as plasma spraying to engineer the substrate-coating-bone interface in such a way to realise optimal implant fixation in combination with an additional bioactivity and biofilm inhibiting functionality. Nanocoatings deposited by combined metal and bioactive powder spraying will be investigated. O5 The development of coating techniques which are radically new for implants such as electrophoretic deposition, selective laser sintering and structuring, dip-coating, plasma enhanced chemical vapour deposition and laser assisted microwave processing that would allow to engineer the substrate-coating- bone interface in such a way to realise optimal implant fixation in combination with osteointegration and biofilm inhibiting functionality.

Project Presentation 9 Scientific & technological objectives NoDescription O6 Microstructural characterisation of the BAG, calcium phosphate and titania based advanced multi-functional substrate-coating systems. O7 Mechanical characterisation of the BAG, calcium phosphate and titania based advanced multi-functional substrate-coating systems. The targeted adhesion strength is > 20 MPa for calcium phosphates and BAG, and > 40 MPa for porous Ti. The targeted adhesion strength for the multifunctional coating is 30 MPa O8 Modelling of thermal residual stresses, thermal treatments and material stability to assist coating design and engineering. O9 Study the importance of the composition and physicochemical properties of various substrate-coating systems produced by partners in the consortium on biofilm formation. Model micro-organism systems which closely simulate the in vivo or in situ conditions for each device will be used. O10 To investigate and select the most suitable anti-microbial substances active during a reasonable and optimal period to reduce infection and biofilm formation to a minimum, and to investigate the impregnation and release of these selected anti-infectives from the new substrate-coating biomaterial systems in vitro.

Project Presentation 10 Scientific & technological objectives No Description O11 The best anti-infective/biomaterial combination will be tested in the Fisher rat model to confirm the in vitro results to validate the biofilm reactor approach by means of in vivo studies carried out using a unique ex-germ-free Fisher rat model. O12 Biocompatibility testing of cell cultures of powders, abrasion debris and substrate/coating systems to study the cytotoxicity of raw materials in an early stage of the project, and to evaluate the various substrate/coating systems and their abrasion debris to determine which are most relevant for bone regeneration and repair in order to select the most promising systems. O13 In vitro bioactivity testing of coating/substrate systems to investigate the bioactivity and bioresorbability of the various coating-substrate systems with and without antibacterial substance, in order to evaluate their osteogenic potential and select the most promising systems for in vivo testing. O14 In vivo testing of bone bonding of the multifunctional coating/substrate systems using an adult rabbit model O15Feasibility study of the upscaling of the coating technologies for the coating of implants

Project Presentation 11 MEDDELCOAT consortium LEMI

Project Presentation 12 Project structure & partner co-operation Substrates & powders Coating and sintering technology Characterisation and evaluation Modelling Bacteria-material interaction Biocompatibility testing Dissemination and exploitation (all partners) LIMA, Helipro, KUL Alhenia, AMES, KUL-MTM, UoB, IJS IMMG, KUL-MTM, UoB, IJS LIMA, HUT, KUL-MTM, UoB KUL-REGA, OctoPlus LEMI, Helipro, IJS, KUL-MTM Coating design & Engineering (all partners) Training activities (all partners) Selection of implants(LIMA, Helipro) Substrates & powders (WP1) Coating and sintering technology (WP2) Characterisation and evaluation (WP2) Modelling and finite element analysis (WP2) Bacteria-material interaction (WP3) Biocompatibility testing (WP4) Upscaling feasibility (WP5) all partners LIMA, HeliPro, AALTO KUL-MTM, ALHENIA, UoB ALHENIA, AMES, KUL-MTM, UoB, IJS IMMG, KUL-MTM, UoB, IJS LIMA, AALTO, KUL-MTM, UoB KUL-REGA, HEMOTEQ LEMI, HeliPro, IJS, KUL-MTM Coating design & Engineering (WP2) all partners Training activities (WP7) all partners Selection of implants (WP1)(LIMA, Heli Pro) RTD-activities (WP1-WP5) all Innovation-related activities (WP6) all Demonstration activities (WP8) all

Project Presentation 13 Project work plan overview Task 2.2: Coatings for implant fixation Task 2.3: Bioresorbable and bioactive coatings Task 2.4: Thermal treatments Task 2.5: Structural characterisation of coating/substrate systems Task 2.6: Mechanical characterisation of coating/substrate systems Task 2.7: Modelling and finite element analysis & thermodynamic and kinetic modelling Task 2.1: Coating engineering & design WP 2: Coating of implants WP 3: Bacteria-coating interaction WP 4: Biocompatibility and activity testing Task 3.1: Bacteria-coating interaction investigation Task 3.2: Selection and incorporation of biofilm inhibitors Task 3.3: Evaluation of biofilm inhibiting coatings Task 4.1: Cell culture of powders and coated implants Task 4.2: Bioactivity and resorbability testing of coatings Task 4.3: In-vivo testing of bone bonding WP 1: Substrates & bioactive powders Task 1.1: Selection & supply of substrates and implants Task 1.2: Selection & supply of bioactive powders WP 5: Upscaling feasibility WP 6: Innovation related activities WP 7: Demonstration activities WP 8: Training activities WP 9: Project management

Project Presentation 14 Project milestones NoMonthDescription M00Signed Consortium Agreement (All Partners) M118 Supply of state-of-the-art dental and shoulder implants and hip stems and acetabular cups (HeliPro, LIMA) M212 Development and supply of a range of bioactive powders (Alhenia, KUL-MTM, UoB) M36 Initial composition definition of the graded Ti metal/bioactive material coating (All Partners) M46 State-of-the-art vacuum plasma sprayed calcium phosphate and Ti + HA coatings as a reference for biofilm formation investigation (WP 3), coating adhesion testing and biocompatibility and activity investigation (Alhenia) M518 Supply of the first multi-functional (fixation + bioactive) substrate-coating combination (KUL-MTM, IJS, UoB, Alhenia) M624 Supply of the first generation of multi-functional (fixation + bioactive) substrate- coating combination for each processing route (KUL-MTM, IJS, UoB, Alhenia) M724 Microstructural characterisation of the vacuum plasma sprayed state-of-the-art coatings and the first advanced multi-functional substrate-coating systems (IJS, KUL-MTM, UoB).

Project Presentation 15 Project milestones NoMonth Description M8M830 Nanoscale microstructural characterisation of the vacuum plasma sprayed state- of-the-art coatings and the first generation of advanced multi-functional substrate- coating systems (IJS). M9M924 Mechanical characterisation of the first generations of advanced multi-functional substrate-coating systems (IMMG). M1018 Micromechanical and finite element model for the evaluation of the thermal residual stresses and thermal treatments of the envisaged substrate/coating systems. (AALTO) M1124 Assessment of the physicochemical properties of biomaterials which limit the adherence of micro-organisms to the substrate, and hence, will avoid biofilm formation. (KUL-REGA) M1224 Knowledge on the best anti-infective/biomaterial combination and formulation for an efficient prophylactic and therapeutic action (KUL-REGA, HEMOTEQ) M1336Biofilm inhibitor formulation (HEMOTEQ) M1445Biofilm inhibiting coatings evaluated in vivo. (KUL-REGA) M1518 Evaluation of cytotoxicity testing of bioactive starting powders and substrates (LEMI)

Project Presentation 16 Project milestones NoMonth Description M1630Evaluation of cytotoxicity testing of the new coating-substrate systems (LEMI) M1736 Biocompatibility evaluation of the abrasion wear debris generated in the pin-on- flat tests (LEMI) M1824 In vitro bioactivity evaluation of state-of-the-art vacuum plasma sprayed and the first generations of multi-functional coating/substrate systems (LEMI, KUL-MTM). M1936 Evaluation of bioactivity testing of the substrate/coating systems (LEMI, KUL- MTM) M2045 Evaluation of bone bonding of the multifunctional substrate/coating systems (Heli- Pro, IJS, KUL-MTM) M2145 Feasibility study for a continuous microwave heating system for the coating of implants with different geometries (AMES) M2242 Feasibility study for the upscaling of the coating processing routes for implants with different geometry (KUL-MTM, IJS, UoB, Alhenia) M2324Critical progress review milestone (all partners) M2436 Selection of the multifunctional substrate/coating systems for in vivo bone bonding testing (all Partners).

Project Presentation 17 Expected impact of the MEDDELCOAT project Community societal objectives –The project aims at a drastic decrease of implant failures, concomitantly reducing the number of revisions, lowering the pain and suffer of the patients and decreasing the medical costs for patients and community. –The implementation of highly reliable implants definitely improves the mobility and quality of live of those among us who need it because of age, illness or accident. –SME-driven market ! Small and medium size companies together make up more than 80 % of medical technology business entities. This industry contributes significantly to saving life and improving the quality of life of the citizens of Europe. –SMEs are the main job creators of European industry. MEDDELCOAT will enhance the ability of the SMEs involved to improve their competitiveness, with an immediately positive effect in job creation.

Project Presentation 18 Expected impact of the MEDDELCOAT project Contribution to policy developments –The project addresses the integration of nanotechnologies, material science and advanced technologies to improve health and quality of life of European citizens and creating wealth through novel knowledge-based and sustainable products (biomaterials) and processes (coatings). –The project will contribute to a dynamic and competitive knowledge- based economy (“Lisbon” objective), sustainable development (“Göteborg” objective), and serves the needs of a traditional SME- intensive industrial sector. –The project contributes to the ERA by focussing on nanotechnologies, intelligent materials and new production processes; sustainable development; genomics and biotechnology for health; and citizens and governance in the European knowledge- based society (4 of the 7 research priorities for Europe) and especially enhances the participation of SMEs in ERA.

Project Presentation 19 Expected impact of the MEDDELCOAT project –Biomedical implants are knowledge-based products with high added value. At present, about 60 % of the implant market in Europe is controlled by non-EU companies. The development of a technology, as envisaged in the IP-SME project, would give competitive advantage to European SMEs which is of high interest not only to conserve employment, but also to create new jobs in Europe. –The proposed research is of strategic importance to the EU in view of the massive impact on market share which would result from the development of the envisaged biomaterials with multifunctional bioresorbable biocompatible coatings with biofilm inhibition and optimal implant fixation.

Project Presentation 20 Expected impact of the MEDDELCOAT project Gender issues –The goal within this project is to reach a minimum of 25 % of female researchers at the recruitment stage and encourage greater participation at senior level, which is significantly higher than the European average of 15 % for industrial research. Contribution to standards –The activities related to the bacteria-material interaction investigation, the development and evaluation of coating integrated biofilm inhibitors, and biocompatibility testing will result in an active participation in European and international standardisation committees.

Project Presentation 21 Expected impact of the MEDDELCOAT project Economic impact –The $80B medical device industry continues to grow at 9 % per year, driven by the aging global population and medical advances. – Less than 5 % of the medical device market now utilizes surface modification technology of any kind. As the demand for better, more advanced biomaterials accelerates in step with scientific breakthroughs, the market for surface modification of existing medical devices is expected to grow at approximately 80-90% per year for the next 5 years, as the market adopts "intelligent" coatings. –Early adopters will use the coatings to either improve device biocompatibility or reduce infection; later generations of coatings could conceivably employ a nearly infinite array of therapeutic agents. We anticipate that "intelligent" coatings for medical devices and biologic implants will become the standard of care.

Project Presentation 22 Administrative information Project –Type: IP-SME –Contract no.: NMP3-CT – Project duration: 01/10/2006 – 31/3/2011 No. of person-months: 674 Budget: –Total project budget: 4706 k€ –EC funding: 3300 k€ Project co-ordination: K.U.Leuven R&D (Leuven, Belgium)

Project Presentation 23 Contact For further information –Visit: –Project coordinator: Prof. Dr. ir. Jef Vleugels Katholieke Universiteit Leuven Departement of Metallurgy and Materials Engineering (MTM) Kasteelpark Arenberg 44, B-3001 Heverlee (Belgium) phone: , fax: LEMI