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New Generation of orthopaedic Biomaterials

Final Report Summary - NEWBIOGEN (New Generation of orthopaedic Biomaterials)

Executive Summary:
Biomaterials industry and especially the orthopaedics sector represent a large market globally with growth rates of 7-15%. Unfortunately current biomaterials are not optimal and cause pain and distress to a large number of patients. Particularly their life cycle is very small compared to the average starting age of musculoskeletal disorders. The raw materials used can cause neurological problems as Alzheimer disease due to metal ions released in the body and the stress shielding effect can lead to bone atrophy. Also the structural and mechanical properties of biomaterials used in implants are not optimal, chemical inhomogeneity and large distribution of porous dimensions are common factors in production process. There is a clear need for innovation in biomaterials production in terms of biocompatibility, mechanical, and surface properties. NewBioGen introduces a new biomaterial production process that will solve the current problems and provide a new generation of orthopaedic bio-implants. Beta titanium alloys, containing fully biocompatible elements, will be optimised and validated as raw materials for the biomaterial production. The new production process will be using powder metallurgy technology. Use of powder metallurgy for bio-implants production will allow increased control of the final characteristics and properties of the product. It is expected to significantly reduce the chemical and porous inhomogeneties - a source of stress and cause of mechanical implant failure. The next step in our novel approach is the application of ZrO2/Zr coating on the implant using Laser Engineered Net Shape techniques to give better wear resistance and lower the possibility of interfacial separation under repeated loading condition.
Project Context and Objectives:
The main axis of NEWBIOGEN project is the utilization of a beta Ti35Nb6Ta alloy as raw material for developing improved orthopaedic implants regarding tribology, mechanical properties, lifecycle and biocompatibility. The aforementioned beta Ti35Nb6Ta alloy has several advantageous properties over the currently used Ti6Al4V and Ti6Al7Nb. Firstly, all the alloying elements are cytotoxicity free and the material is expected to have excellent biocompatibility. Ta is immune to all acid environments, enhancing the corrosion resistance of the material in the human fluid environment which has various pH values from 3.5 to 9. Secondly, it has a significantly lower elastic modulus than alpha Ti alloys, which can diminish “stress shielding effect”. It has been shown that the elastic modulus of a Ti35Nb6Ta can be as low as 50GPa, which is close to those of human bones (~20GPa for cortical bones).Thirdly, both Nb and Ta improve the density and strength of surface Ti oxide passivation film, which reduces the release of metal ions and enhances material’s in-vivo corrosion resistance. Finally, the alloy has a large widow for property improvement during thermomechanical processing. Upon heat treatment or thermal processing including forging and sintering, solid state phase transformation may occur. Proper combination of processing parameters can lead to microstructural refinement and homogeneity with improved physiochemical and mechanical properties.

Ti alloys are normally manufactured by arc melting before casting. However, beta stabilizers including Nb and Ta have apparent high densities and high melting points than the alpha Ti phase, which can cause severe chemical segregation. Multiple melting and casting procedures of up to eight cycles have to be employed to achieve homogeneous chemistry. Through this route, the resultant microstructure is often dominated by coarse dendritic grains, which has advert effect on mechanical properties. Overall, this route is expensive and inadequate for property control. Powder metallurgy technology offers perfect solution for the above problems by the direct mixing of alloying element powder under controlled conditions, although the control of porosity volume fraction, size and distribution is a big challenge. Porosity in orthopaedic implants affects both mechanical properties and bioactivity such as tissue ingrowth .In this project, a new porous Ti35Nb6Ta alloy is manufactured using a novel powder metallurgy process and its related machinery, which has been described in separate reports.

Although the Ti35Nb6Ta alloy is superior to the currently used Ti6Al4V and Ti6Al7Nb in mechanical and biological properties, their tribological properties are similar. In this project, a Laser Engineered Net Shaping (LENS) technology has been used to apply a ZrO2 coating on the Ti35Nb6Ta implants. The application of a strong and tough ZrO2 coating is expected to largely improve the wear and corrosion resistance and other tribological performance of the Ti35Nb6Ta implants. The utilization of LENS technology has an advantage of reducing interfacial separation between the coating and the matrix, which is a common problem for the current coatings. In the coating process, pure Zr is deposited initially on the implant by LENS and then oxidized under an optimized pressure. As a result, the implant is covered with a coating of ZrO2 film on top of the Zr layer. Below are mentioned the objectives of the project per Work Package.

During workpackage 1, the specs related to the orthopaedic biomaterials, industrial equipment and titanium alloys requirements were set. The main objectives that which required to be completed during this WP is the identification of the specs regarding
1. Mechanical properties of biomaterials: creep, fatigue, elastic modulus, ductility, tensile strength,
surface hardness
2. Non mechanical properties of biomaterials
3. Design of the implant which will be developed
4. mixing equipment requirements
5. packaging system requirements
6. powder filler requirements
7. cold isostating press requirements
8. sintering furnace requirements
9. fabrication process for titanium alloy requirements
10. hardness rating, shear modulus rating and poisons rating for titanium alloys

During work package 2 the investigation of production process parameters was implemented. The objectives that were set to beimplemented during this WP are the following:
a) several samples were developed combining the below mentioned parameters grain sizes, several mixing times, different pressures, compaction times, sintering temperatures: 1000 and several sintering durations.
b) All the aforementioned samples were characterized by SEM, XRD, hardness, Young Modulus, porosity and density in order to identify the ones that have lower young modulus, enhanced mechanical properties etc.
c) a simulation model of powder metallurgy process using the data of tasks 2.1 and 2.2.

During workpackage 3 a final detailed design of the mixing, filling and sealing systems was set to be developed along with the construction of the corresponding prototypes. The main fulfilled objectives that were designed to be implemented in this WP are the following:
a) a mixing equipment utilizing a 3-phase AC motor having a mixing capacity of powder between 3-10 Litres considering a 70% of barrel loading.
b) a packaging filling equipment with the following characteristics: Stage 1 hopper’s capacity is 3.34Lt
c) a sealing equipment with the following characteristics: designed to accommodate bags’ width range between 50 and 180mm

During work package 4 a final detailed design of the feeding system, cold isostatic pressing system, heavy duty glovebox, sintering furnace and main control system was designed to be developed along with the construction of the corresponding prototypes. The main implemented objectives of this WP are the following:
a. a feeding system with the following characteristics: feeding capacity is 3.13Lt
b. a cold isostatic system with the following characteristics : provides consistent isostatic pressing of rubber molds designed to receive molds with dimensions of 45mm diameter and 140 mm length.
c. a heavy duty glovebox
d. a sintering furnace
e. main control system which includes main PLC for stepper motors control, PLC extension for pneumatic valves control, PLC extension for sealing system temperature control, power supply units etc.
f. design and development of rubber molds with thickness of 1 mm

The main aim of WP5 was to investigate the ZrO2/Zr coating process with LENS technology. During the implementation of this workpackage, pure zirconium was used as powder in LENS equipment for coating the samples with the best properties as defined in Workpackage 2. The main objectives of this WP was to identify if the developed coating had very low wear rate and also if it is non toxic and biocompatible.

During Work package 6, an implant was set to be developed through the experimental rubber molds using the developed machinery. Several mechanical and biocompatibility tests have been designed to be performed in the developed implants in order to identify issues of biocompatibility, cytotoxicity, elastic modulus, yield strength, cell adhesion behaviour etc.

During Work package 7, the main objective was the demonstration of an actual production process among the consortium members which will be recorded

Project Results:
Below, it is described the main scientific and technological results that were implemented during NEWBIOGEN project per

WP1 Generation of requirements and specifications (Start M1-End M3)
The objectives of this WP according to the DOW are mentioned below:
a. define the orthopaedic biomaterials requirements
b. define the industrial equipment requirements
c. define titanium alloy requirements.

Task 1.1. entails the identification of biomaterials requirements. During this task, the literature was reviewed and the partners contributed information according to their experience. The main mechanical and non mechanical properties of the biomaterials have been identified. Additionally, an implant was designed that will be manufactured in WP 6 and WP7. The results of this task have been included in the deliverable D1.1.

Task 1.2 entails the identification of the process which is used so far for the manufacturing of implants. Additionally, specs of the systems that will be developed in WP3 and WP4 have been set. The results of this task have been included in the deliverable D1.2.

Task 1.3 includes a brief overview of all type of titanium alloys used so far. Additionally, it is mentioned how the production process has the capacity to influence the final properties of the titanium alloys. Last the titanium alloys specs have been identified in regards with microstructure, shear modulus etc. The results of this task have been included in the deliverable D1.3

2 WP 2 Investigation of production process parameters (Start M3- End M9)
The objectives of this workpackage according to the DOW are the following:
a. Production of several samples under different manufacture parameters
b. Characterization of the samples
c. Define optimum parameters in relation to the objectives set in the DOW
d. Develop a simulation model of powder metallurgy production process.

Task 2.1. Production of samples
The parameters that have been combined in order to develop different samples of titanium alloy are mentioned below:
1. grain sizes: i)smaller than 40μm, ii) 40-80μm and iii) 80-125μm
2. several mixing times: 1 h and 2 h
3. different pressures: 200-450MPa
4. compaction times: up to 1 minute
5. sintering temperatures: 1000 and 1100oC

After the development of the samples following all the aforementioned different parameters, several characterization tests have been implemented during task 2.2. such
as XRD analysis, tribological analysis, corrosion measurements, elastic modulus, micro hardness and others in order to identify the samples that address DOW's criteria and define the optimum production parameters. It was concluded that the samples M15, L17 and L15 have the best properties.

Task 2.2. Characterization of samples
All the samples developed during task 2.1. were characterized by
1. measuring the dimensions before and after sintering
2. measuring the apparent density
3. scanning electron mesurements – EDX analysis
4. XRD analysis
5. Hardness (Vicker’s)
6. Young’s modulus
7. Porosity
8. tribolobical studies
9. Cytotoxicities studies

The results of the aforementioned tests indicated that M15, L15 and L17 are the optimum ones.

Task 2.3. Simulation model of powder metallurgy
During this task, the data gathered in tasks 2.1 and 2.2. were processed in order to correlate the production parameters with the properties of the final product. Two differ ent models have been used, fuzzy model and Artificial Neural Network, in order to validate and evaluate which model is more accurate. It was concluded that Fuzzy mod el is more accurate. Thus, the fuzzy-rule based model was employed to develop the Newbiogen software prediction tool. The software was implemented in MATLAB® language and it is based on the mathematical model and numerical method described in the section 4. The software aims to predict the elastic modulus and microhard ness of the product when the values of different production parameters change. An easy-to-use graphical interface was developed in order to allow implant manufacture rs to use it, without requiring any software knowledge. Moreover, it can be used with small modifications for other applications that use powder metallurgy.

WP 3 Development of mixing and packaging machinery (M8-M15)
The main objectives of Work Package 3 as mentioned in the DOW are the following:
1. Development of a mixing equipment
2. Development of a packaging equipment
3. Integration in a fully automated machinery
The aforementioned objectives have been successfully accomplished. Below are more details regarding the process that was followed and the results that have been obtained.

Task 3.1 b. Development of a mixing equipment
The development of the NewBiogen mixing system was initiated with the definition of the design specifications which cover a range of functional, efficiency and safety requirements. Based on the compiled list of specifications different engineering solutions were considered before finalizing the design concept. The system was designed and all required components were selected (motor, machine elements, etc.). Construction materials were also defined. Detailed mechanical drawings were prepared using 3D Computer-Aided-Design (CAD) tools from which the required 2D blueprints were produced. The CAD software allowed to visualize and evaluate the design, confirm selection/sizing of its components as well as identify required design modifications. Upon finalizing the design the manufacture and assembly of the device was carried out. The main result of this task is the development of a mixing system with characteristics mentioned in detail in the deliverables of WP3.

T3.2b.Development of packaging-filling equipment
The Newbiogen filling system is based on drum feeder technology. The designed filling system is a space-saving solution for discharging various quantities of mixed powder with accuracy and high efficiency. It has been designed to serve two different discharging functions. Particularly, the designed filling system can be set up to manage multiple dosages, so as to enable either the filling of rubber molds (for isostatical cip pressing) or the filling of bags that will be sealed and stored for later use. The Newbiogen filling system is controlled by the main control system which generates all appropriate signals for achieving a repeatable filling cycle each time. The main result of this task is the development of a packaging filling system with characteristics mentioned in the deliverables of WP3.

T3.3b. Design and construction of sealing system
The designed and constructed NewBiogen sealing system is an easy-to-use, jaw-type, heat sealer operated by a foot pedal-activated pneumatic system and controlled by the main control system. It is designed for use on heat-sealable materials up to 300μm thickness, including polyethylene and similar plastic materials. The system was designed and all required components were selected (pneumatic pistons, machine elements, thermocouples etc.). Construction materials were also defined. Upon finalizing the design the manufacture and assembly of the device was carried out. The main result of this task is the design and construction of sealing system with characteristics mentioned in detail in the deliverables of WP3

T.3.4b. Integration and optimization
The WP3 systems were constructed taking into account the final fabrication designs, the assembly specifications and tolerances, the constraints and the feedback from the SMEs regarding the selected components, the usability, appropriateness, integrability and the performance of the complete machinery equipment. During the integration phase, adjustments and fine-tuning of each system was carried out. Testing of the complete Newbiogen machinery allowed optimization of functionality and improvement of performance parameters.

WP 4 (Start M8-M20) Development of automated scale-up production machinery for implants
The main objective of work package 4 according to the DOW is the development of automated production machinery for implants. The aforementioned objective has been implemented successfully. More information regarding each system and the main results derived, are described below.

T.4.1.B. Development of feeding system and molds
The designed and constructed Newbiogen feeding system has an in-line structure and is responsible for receiving the mixture from the mixer (lowest position) and then for depositing it automatically to the hopper of the filling system (upper position).
The system measures the weight of the mixed powder at the loading station using a load cell and an automatic releasing system of the bucket at the lowest position. The weighing of the mixed powder is necessary in order to ensure that the correct powder quantity is discharged by the mixer, according to the pre-set quantity selected on the touch screen. The operation of the Newbiogen feeding system is controlled by the main control system. The feeding system as well as the mixing, filling and sealing systems are enclosed into the glovebox. The rubber molds of hip implants were designed taking into account the input given by Socinser regarding the geometry of the implants as well as the experimental compression ratios derived from WP2 (top pressing in metal molds) and the calculated compression ratios for CIP pressing. Other results of this task is the development of a feeding system as well as the design and construction of the molds. The specifications of the developed feeding system are mentioned in detail in the deliverables of WP4.

T4.2.B. Development of cold isostatic pressing equipment
The designed and constructed NewBiogen cold isostatic pressing system (CIP press) is based on the wet bag technique. It uses hydraulic oil as a working medium to apply hydrostatic pressure to the forming mold which is sealed airtight outside the high-pressure vessel before direct immersion into a pressure medium. The applied hydrostatic pressure transmits pressure uniformly in all directions and can form the enclosed mixed powder into a solid shape using isostatic actions. Thus, the result is a compressed part with uniform material properties along all directions. The Newbiogen CIP press was designed and constructed taking into consideration the design specifications which cover a range of functional, efficiency and safety requirements as well as the results derived from WP1 and WP2, especially with regards to the applied pressure.
The main features of the Newbiogen CIP press are the following:
• Homogeneity. Due to isostatic pressure, the part has a constant density in all directions.
• Density. High density molding is achievable.
• Processing: Accurate process due to the high isostatic pressure.
The main result of this task is the successful development of Isostatic Cold Pressing system with characteristics mentioned in the deliverables of WP4

T.4.3.B. Construction of heavy duty glovebox
The designed and constructed NewBiogen glovebox is a heavy duty enclosure whose structural elements are able to hold more than 1ton weight of machinery equipment. The NewBiogen glovebox uses the evacuation/refill method, with a positive pressure gas inside the chamber and a negative pressure vacuum, allowing the main chamber of the glovebox to be filled with the Argon gas.

The design and construction of glovebox arose, after the completion of WP2 which resulted in very strict requirements regarding the conditions of mixing, filling and sealing. After a thorough discussion with the SMEs during 12M meeting and through teleconferences, it was decided that the best solution, would be the design and construction of a heavy duty glovebox, in which the mixing, filling, feeding and sealing systems will be enclosed. This configuration would better serve the scope of the whole process.

Through the implementation of the project and after the trials and the tests it became apparent that Newbiogen glovebox makes the manipulation of the individual systems very efficient, effectively protects the powders from oxidization and contamination and has the potentials to be used in a scaled-up production line since its specifications are noteworthy.
All operations with the exposed powders (mixing, filling, feeding and sealing) are executed into the glovebox in order to avoid oxidization of the powders. The molds are exited from the glovebox using the two ante-chambers.

The main result of this task is the successful development of a heavy glove box with the specifications mentioned in the deliverables of WP4

T.4.4.B. Development of main control system
The operation of the system and interaction with the user involves a touch screen. It is used for entering the user input, operating parameters for every individual system that is enclosed into the glovebox, as well as to display functional information regarding the status of the complete system. For ergonomic purposes the touch screen fixture can be adjusted to operators’ position on both sides of the glovebox (front and rear side). User input devices also include two foot pedals (one for filling the bag with powder and one for activating the sealing jaws) and a number of appropriately located emergency stop buttons as required for safety purposes. Controlled operation is based on sensory feedback information from a number of installed proximity sensors that identify the position of all moving components. Feedback sensors also include load cells for measuring material quantities when required, as well as temperature measurements from the thermocouples installed on the jaws of the sealing system. The control logic is implemented on a Programmable Logic Controller (PLC) system. All components associated with the controller are collected inside a cabinet. In more details, the main control system includes the following components:
• Main PLC for stepper motors control (XINJE 240V - 18 inputs, 14 outputs)
• PLC Extension for pneumatic valves control (36 outputs)
• PLC Extension for sealing system temperature control (6 channels)
• Power supply units (5V DC, 24V DC, 40V AC)
• Stepper motor drivers (X3)
• Inverter for AC mixing motor control
• Circuit breakers for protection/safety
• Contactor for emergency stop
• Solid-state relays for temperature control (X2)

T.4.5.B. Development of sintering system
The designed and constructed sintering furnace is appropriate for the heat treatment of 10 isostatically compressed hip implants. The sintering furnace is used for the shaping and forming of green parts by heat to the point of liquefaction, without reaching the melting point of the materials. The melting points of Newbiogen materials are: Ti:1668 °C, Ta: 3020 °C, Nb: 2469 °C. The desired temperature of the furnace, as resulted from WP2 experiments, should be around 1100oC. For that reason the Newbiogen furnace is designed to achieve 1200oC. During the heating process, atomic diffusion drives powder surface elimination and consequently densification-solidification. The driving force for densification is the change in free energy from the decrease in surface area and lowering of the surface free energy by the replacement of solid-vapor interfaces. For the achievement of enhanced mechanical properties such as strength, hardness and fracture toughness the bond area in relation to the particle size is the determining factor. According to WP2, by applying temperatures around 1100oC, for 6 hours under Argon atmosphere, the atoms in the materials will diffuse across the boundaries of the particles, thus fusing the particles together and creating solid and stiff hip implants. The aim is to reduce the porosity of hip implants, increase the density and enhance mechanical properties such as strength, hardness and fracture toughness. The variables that can be controlled using the Newbiogen sintering furnace are the temperature, the sintering environment, the duration of heating as well as the heating and cooling cycles.

The main result of this task is the successful design and development of a sintering system with the following specifications:
• Heating chamber dimensions: 400x300x300mm
• Heating chamber structure: double shell with fan cooling that is able to reduce temperature quickly
• Materials. Shell: High strength steel, Insulation: Alumina ceramic fiber
• Designed to be filled by argon gas in order to avoid oxidization. The desired atmosphere is achieved by valve and flow controller.
• Heating element: resistance wire
• Thermocouple: K type
• Electrical elements: Power relays, exchange contactors, resistances, sockets, switches etc.
• Maximum designed temperature: 1200oC
• Working temperature: 1100°C continuous
• The temperature can be controlled using a digital controller that automatically changes the heating temperature as well as the heating and cooling cycles. The selected microprocessor based controller combines a high degree of functionality and reliability. The controller is built in PID Auto-Tune function with overheating & broken thermocouple protection.
• The 3-phase current is measured using 3 analog ammeters (one for each phase) that housed inside the control cubicle that mounted at the bottom compartment of the furnace. The voltage is measured using an analog voltmeter that also housed inside the control cubicle

T.4.6.B. Integration of implant production machinery
During the integration phase several adjustments and fine-tuning were conducted for each system. To achieve savings on resources and materials usage, the full system testing, with the aim of process verification, was conducted using fine-grained bronze powder, which has comparable properties to the very expensive Newbiogen powders. It should be noted that through the results obtained from the individual units and complete system testing, enough knowledge and insight was gained allowing the: a) process verification, b) upgrade in functionality, c) usability enhancements, d) application appropriateness and integrability. These in turn led to performance improvements.

WP 5 Research and development of ZrO2/Zr coating using LENs technology (Start M3- End M9)

The objectives of work package 5 according to the DOW are the following:
a) Define the appropriate thickness and characteristics of ZrO2/Zr coating

Task 5.1. Investigation of ZrO2/Zr coating production parameters with LENS technology
Pure zirconium was used as powder in LENS equipment for coating the samples with the best properties as defined in Workpackage 2. The isolation of commercial zirconnium from its additives was implemented inside the chamber of LENS equipment in non-oxidized environment. The samples were coated in different powers (under Argon atmosphere which resulted in different bonding zones thicknesses.The samples were characterized by XRD, tribological tests and cytotoxicity studies. The results of these studies showed that the wear rate is 0.0015 mm3/NM, the Zr coatings are non toxic and biocompatible. The consortium has also decided to proceed to to investigate the commercial mixture zirconium-yttrium that exists in the market (TZ-3Y and TZ-8Y) in order to have a level of comparison but also to investigate the use of other similar materials for other applications. . Several samples were coated with LENS technology and then subm itted to XRD, SEM tests and cytotoxicity studies. The main result was that either TZ-3Y and TZ-8Y can be used for the second type of coating.

WP 6 Characterization and testing of NewBioGen implants (Start M21- End M26)
The objectives of WP6 according to the DOW entail the implementation of mechanical and biocompatibility tests in the developed implants.

T.6.1.Production of a coated implant by using the manufactured equipment
During this task 6 implants were developed and coated using the manufactured equipment. As explained in WP4, there were several difficulties in the molds manufacture which became obvious during the development of complicated shapes implants. The result was that during demolding process the green implant was destroyed due to inadequate elongation of the latex used in the mold. It was also tried unsuccessfully to cut down the mold during demolding in an attempt to reduce the damage to the green part. Thus, it was decided from the consortium to proceed with the production of implants with cylindrical shape which was simpler and the demolding process did not affect the green part at all.

T6.2. Testing of coated hip implants
The following mechanical tests took place in the developed implant samples
i) hardness test
ii) tensile test
iii) compression test and
iv) Charpy impact tests
Additionally, biocompatibility tests were also implemented in the aforementioned implants such as
i) cytotoxicity assays
ii) indirect contact tests
iii) direct contact tests
iv) Alamar Blue Assay for cell viability and
v) cell attachment

The results of the tests showed that both uncoated and ZrO2/Zr coated β-type Ti-35.5Nb-5.7Ta alloy implants exhibit excellent biocompatibility. Under all tested conditions in direct and indirect contact experiments, the manufactured implants showed no cytotoxicity. The implant surfaces have good cell adhesion and the adhesion behaviour is not sensitive to surface roughness and morphology. Under the optimum conditions, the modulus of the implants was 38GPa from tensile tests and 44GPa from compression tests, which meets the target modulus value of less than 50GPA. The yield strength and ultimate strength of the implants are in the range of 300-338MPa and 340-396MPa respectively, which are adequate for the proposed orthopaedic applications.

WP7 Demonstration of NEWBIOGEN results
The objectives of this WP according to the DOW are mentioned below
1. Produce a coated implant by using the manufactured equipment
2. Prove through testing that NewBioGen implant is better than the commercial ones.
The aforementioned objectives have been successfully implemented as described in more detail below.

T.7.1.Demonstration of production process developing coated implants
During this task, the production of an implant was demonstrated among all the partners of the consortium. The process was recorded and edited.

T.7.2. Comparison of commercial implants with the NewBioGen implant
After the implementation of WP6, it became clear that NEWBIOGEN implant has reached the targeted goals that have been set in the DOW. As such it became crucial to compare the properties but also the cost of the existing commercial implants with the newly manufactured one in the project. Thus, Socinser along with the other partners have provided input to GDT in order to write down in paper the advantages of NEWBIOGEN implant compared with commercial ones. The deliverable 7.2 provides an overview of this work and describes in detail the advantages that NEWBIOGEN implant has regarding the cost, mechanical and biocompatibility properties

Potential Impact:
NewBioGen is a project within the EU Seventh Research Frame Program (FP7) in the area of Research for the benefit of SMEs. NewBioGen aims to develop new biocompatible raw materials, design and manufacture a scale up production process for the development of orthopaedic hip implants and manufacture of implants with low modulus which will be near to the bone (50GPa), not toxic, lower price, enhanced wear resistance and will last more than the current solutions available in the market.

The long term objective of this two-year project is to develop innovative biocompatible orthopaedic implants which will address the public’s needs and will conquer very fast the market bringing great gains to the involved SMEs. Additionally, the novel production technology has a prominent potential to be used with limited modifications for the development of other biomaterials such as dental and knee implants or for applications in other areas such as navy and aircraft manufacturing giving the IEMS more flexibility and market space for business development.

This will be done by using different raw materials such as Ti-35.5Nb-5.7Ta which is not toxic as it contains fully biocompatible elements (Nb,Ta). An advanced surface treatment technology of Laser Engineered Net Shaping (LENS) will be used to apply a high quality Zr/ZrO2 coating on the moving parts between the implant and the bone that need high wear resistance (moving parts of the implant). Moreover, fully automated machineries will be developed for titanium alloy manufacturers and orthopaedic implant industries.

All intellectual property issues are formalized in a Consortium Agreement (CA) which deals with all aspects of ownership and use of Intellectual Property in addition to the management agreements for the project. Several discussions have been made among the SME partners regarding subsequent agreements among them for the further exploitation of the results. The content of the aforementioned discussions are mentioned in the exploitation plan D9.2

The global orthopedic sector is a dynamic component of the medical device industry, which can be broadly divided in two main categories: orthopedic devices, and orthotics and prosthetics. Orthopedic devices include joint reconstruction materials and biomaterials used in the reduction of fracture fragments, bone manipulation and joint replacement. Reduction can be non-invasive, as is the case with external splints and traction, or can involve surgery to implant and replacement artificial joints. In comparison, orthotics and prosthetics involve evaluating, fabricating and custom fitting braces and artificial limbs.

With increase in the percentage of aging population worldwide, the number of individuals suffering from physical disability is also increasing. Baby boomers born between 1946 and 1964 are the major consumers of the biomaterial products. Besides, more than 20% of the global population in 2050 is expected to be over 60 years and this segment (of the population) will be significantly high in developing countries. This increase in the aging population will drive the demand for biomaterial products.

Overall, the orthopedic market felt the effects of the economic crisis, with cuts in medical-care spending and patients more reluctant to undergo optional surgeries due to the lengthy recovery time out of work. Highly competitive and at maturity with a single-digit growth rate, the global orthopedic devices market is primarily driven by: 1) artificial joints, with a worth forecast of almost $17.5 billion by 2012; and 2) orthobiologics, estimated to reach $9.6 billion by 2016, according to Global Markets Direct. Segment growth is also boosted by increases in knee and hip implants, and knee and hip replacements. According to research from Global Industry Analysts, the world orthopedic prosthetics market is expected to hit $19.4 billion by 2015, with growth driven by rising degenerative joint diseases (osteoporosis and arthritis), an aging global population and the desire to keep up an active lifestyle.

The orthopaedic device market is being driven by rising cases of osteoporosis, which the International Osteoporosis Foundation (IOF) reports to affect 75 million people in Europe, the US and Japan. This number which falls in line with current orthopaedic device market shares that put the US in first place followed by Japan and Germany. The foundation forecasts a 310% increase in hip fractures in men and a 240% increase in hip fractures in women worldwide by 2050. Similarly, arthritis is set to continue driving the orthopaedic devices market, with 22% of 50 million adults in the US suffering from the condition, a figure that is predicted to reach 67 million by 2030. Emerging countries - such as China, India and Brazil - are seeing strong growth for orthopaedic devices, with revenue expected to reach $2.9 billion in 2016 for a compounded annual growth rate of 8%, according to GBI Research.

According to the MedMarket Diligence report "Emerging Trends, Technologies and Opportunities in the Markets” [] the current total global value of the biomaterial based medical devices market is estimated to be more than €157 Billion, with annual growth at 15%. Currently, the orthopaedic biomaterials sector represents 16% of the biomaterials total (= €25,12 billion). The current share of Europe in this market is 18% of the global market (=
€4,512 Billion). With a conservative 15% annual growth in 5 years the European orthopaedic biomaterials sector’s value will reach €24,1 billion.
The NewBioGen project is going to produce a new generation of improved biomaterials by modifying the raw materials used, the production line and applying coatings that would provide orthopaedic implants with the following Unique Selling Points:

• non toxic
• long lifetime of at least 20 years
• elastic modulus up to 50GPa
• at least 40% lower cost
• enhanced wear resistance at least 20%
• improved tribological properties
• diminished interfacial separation of the coating
• reduced infections due to the use of biocompatible materials
• reduced risk of osteolysis due to the elimination of metal ions release

Since no current solution in the industry can equal these unique selling points, NewBioGen is going to be considered as a market differentiator and it will be easy for the potential buyers to drop solutions well established in the market. Thanks to the project’s disseminations plan, a major part of the orthopaedic market will be successfully claimed resulting in a reasonable return of investment for the EU and the consortium SMEs.

By analyzing the orthopaedic implants market and taking into account the manufacturing cost of the NewBioGen products, the consortium SMEs have arrived at the prices for the new products. The novel implants will be sold for 3.000€ per implant, a price that is equal to the lower limits of the existing solutions.

In the NewBioGen project, the overall exploitation and dissemination planning has been targeted towards the maximization of the economic benefit for the SMEs as quickly as possible after the end of the project. The NewBioGen project has high research and development content, so full commercialization will require further field-testing to satisfy cost, performance and quality criteria in full-scale production. The consortium is aware of this and appreciates that it is necessary for the product’s development that 2 years are required to fully commercialize NewBioGen after project completion. Besides, these two years will be enough for the European authentication authorities to validate the new orthopedic implants, given that validation tests will start later during the project. The biomaterials used and the manufactured implant will be tested for their biocompatibility, tribological and mechanical properties according to the ISO and ASTM guidelines for biomaterials. The results of these tests will not only be used as a proof for the advantages of the new implant and biomaterial during this project but also afterwards for the authentication process. Toxicity, porosity tribological and wear resistance, tests will take place during the project, while tests on animals will last during the 2 years after the project’s completion. Thus the first product sales are estimated to take place in 2018.

The consortium of NEWBIOGEN project has participated in several events in order to promote its results. In more details, the events that the consortium participated are mentioned below:
1) 2nd International ROMCEN Conference 24-25 June 2014 Calimanesti Cozia, Romania
2) 4th International Symposium on Green Chemistry for Environment, Health and Development 24-26 September 2014 Kos Island Greece
3) International conference "EuroCoalAsh" 14-15 October 2014 Munich Germany
4) Innovation Forum 2014 19-21 December 2014 Athens Greece
5) 6th Welding & Foundry Excibition 21-24 April 2015 Celje, Slovenia
6) 10th National Scientific Conference on Chemical Engineering 4-6 June 2015 Patra,
7) 4th National Conference of EVIPAR (Industrial by-products research and development non profit scientific association) 11-12 June, 2015 Thessaloniki, Greece
8) EAST (European Academy of Surface Technology) FORUM 2015 25-26 June 2015 Lund, Sweden
9) MED TECH Europe 6 October 2015 Ireland
10) EURO PM2015 Congress and Exhibition 4-7 October 2015 Reims, France

Additionally, a website has been developed for the project along with flyers and posters in order to promote further the project results.
List of Websites: