FP-00009

Section 1 - Basic information about you and your application:

Title of research project
Rapid solidification technology for durable and biofilm resistant titanium alloy implants

Grant Type
The ORUK Inspiration Fund

Research area
Treatment

Duration
12

Start date
March 1, 2024

Have you previously received funding from ORUK?
No.

Profession
Academic scientist

Your current job title/position
Senior lecturer/Assistant Professor

Are you an early-career researcher (ECR)? (definition of ECR)
no

Section 2 - Lay summary

Lay summary:

We are aiming to solve three key problems related to prosthetic joints:

1. To minimise the risk of infections of orthopaedic implants
2. To prevent the mechanical non-compatibility between bone and titanium-based orthopaedic implant by decreasing the stiffness of the implants to match that of the bone.
3. To enhance implant durability by increasing their wear resistance and strength.

Global Burden of Disease (GBD) 2019 data [Institute for Health Metrics and Evaluation (IHME). GBD 2019 Cause and Risk Summary] showed that approximately 1.71 billion people globally live with musculoskeletal conditions. Musculoskeletal (MSK) disorders cost to the society about US $ 180 billion (~£141.6) worldwide every year [JAMA Network Open. 6 (2023)].

An estimated 8,500 hip revision procedures are conducted in UK each year at a cost to the NHS of ~£18,000 per hip replacement. Revision surgery carries much higher risks of infection and other complications compared to first time surgery, and the recovery period is longer and more painful.

Almost one third of the population in UK, over 20 million, have a MSK condition such as arthritis or back pain. This results in over 30 million working days lost due to MSK conditions every year in the UK and they account for up to 30% of GP consultations in England [NHS 75 England]. About 300,000 people acquire infections in hospitals each year, which results in ca. 5,000 deaths. The market for medical devices in UK is strong, being the sixth largest medical device producer in the world in 2015 with £7.68 billion contribution to the UK economy but it is facing increasing competition from abroad, especially from the U.S. The development of long lasting antimicrobial and cost-effective surfaces is highly relevant to the NHS and revenue is expected to show an annual growth rate (CAGR 2023-2028) of 3.82%, resulting in a market volume of US$21.13bn (£16.62 bn) by 2028 [Statista. Medical Devices UK].

Our ambition is to develop novel titanium-based implant microstructures by harnessing the cooling rate and the composition of metal alloys to achieve highest combined performance in terms of low stiffness, high wear resistance and specific strength and biofilm resistance. Reducing the risk of healthcare-associated infections attributed to indwelling orthopaedic implants while enhancing their mechanical performance will have a positive impact on patients’ wellbeing by minimising inflammation, pain and also all the problems associated with the need to visit the hospital.

We will run one Patient and Public Involvement (PPIE) event at the end of the project by having access to a relevant group through the Newcastle Biomedical Research Centre (BRC): Patient and public Involvement and engagement in Musculoskeletal reSearch (PIMS) – NIHR Newcastle Biomedical Research CentreNIHR Newcastle Biomedical Research Centre

Section 3 - Purpose of research

Purpose of research:

The aim of this project is to harness the cooling rate when casting Ti-3.5Cu [1], Ti-2Ag [2] and Ti-3.5Zn wt. % alloys to optimize the microstructure to achieve maximum combined performance in terms of low stiffness, wear resistance, high specific strength and biofilm resistance.

The objectives to achieve this aim are:

1. to produce the Ti-based alloy compositions at different cooling rates through control of the casting diameter and the chiller conditions (on and off).
2. To assess the mechanical and biological performance.
3. To select samples whose microstructure delivers the best combined performance. The results will be used as a proof of concept to apply for further funding, including Innovate UK, to translate them into products.

Deliverables:

DL1 (end of week1): Samples produced.

DL2 (end moth 5): Data collected from the microstructures and the mechanical tests.

DL3 (end of month 12): Collection of biology data. PPIE event and a short questionnaire to get feedback from the participants. First draft scientific publication ready and draft paper for Frontiers for Young Minds. Written plan for further funding application.

 

References

[1] Bioactive Mat. 3 (2018) 28.

[2] Mater Sci Eng C 105 (2019) 110059.

Section 4 - Background to investigation

Background to investigation:

The Principal Investigator Dr. Sergio Gonzalez is Senior Lecturer at Northumbria University. His research focuses on the development of novel metallic alloys obtained by rapid solidification and on their structure-processing-properties relationship. He has published more than 68 peer-reviewed research papers (H-index 20). He has received funding as PI from different funding bodies in various countries. From UK: Royal Society International Exchanges (£5,996), Innovate UK Smart Grant 53662 (£180k), EPSRC First grant scheme EP/P019889/1 (£100k), Royal Society Early Career Researchers RG2015R2 (£15 K) and IOP Early Career Researchers Fund (UK) and Co-I on the following projects: Intensive Industrial Innovation Programme (IIIP) (£56.6k) and KTP project (£129.6k). He received a Juan de la Cierva Fellowship (£91k) from the Spanish government to work on the project “New metallic alloys for biomedical applications” to develop biodegradable Mg-based alloys and Ti-based alloys for implant applications. Selected relevant publications from this project: [1-3]. In addition, he has participated as Co-I in the European project: Marie Curie Initial Training Network BioTinet (biocompatible titanium-based structures for Orthopaedics) (£ 20.5M). At Northumbria he has opened a new research strand in antimicrobial surfaces. Selected publications: [4,5]. In addition, he has supervised a thesis in antimicrobial touch surfaces to completion (see file attached).

The co-investigator, Prof. Nick Jakubovics is Professor of Oral Microbiology with >25 years’ experience and >100 publications (H-index 38) in the field of microbial biofilms. He focuses on the application of molecular microbiology tools and biofilm modelling to understand adhesion, colonisation and biofilm formation by medically and dentally important microbes. He has a particular interest in polymicrobial biofilms and microbial cell-cell interactions. His collaborative research on the design of antimicrobial surfaces for medical implants has been funded by multiple grants from EPSRC, industry and Orthopaedics Research UK. He is regularly invited as an international speaker on biofilms research and has been a member of the grant awards panel for the National Biofilm Innovation Centre since 2018. He is also well-connected in the field of dentistry, as Editor-in-Chief of the Journal of Dental Research (IF 6.116) and member of the Board of Directors of the International Association for Dental Research and American Association for Dental, Oral, and Craniofacial Research

Brief literature review:

Rapid solidification (i.e., control of the rate at which a molten alloy cools down) is an efficient method to tune the microstructure of metallic materials since it enables to achieve either a fully amorphous structure (i.e., metallic glass: atoms at random) for high cooling rates or a fully crystalline structure (i.e., atoms are highly ordered) for low cooling rates. At intermediate cooling rates, a mixed microstructure of crystalline phase/s embedded in an amorphous matrix is generally achieved, the so-called metallic glass composites. The resulting microstructure is also compositional dependant since some compositions are more glass-formers than others (i.e., different ability to be obtained in an amorphous state for the same cooling rate). This is important for the performance of an alloy since amorphous and crystalline phases have different properties. In general, an amorphous phase exhibits higher wear and corrosion resistance and lower Young’s modulus than the corresponding crystalline phase. All of these properties are of interest in implants to achieve high durability and match the implant properties with those of the bones (i.e., elastic modulus of 20-30 GPa [6]). However, Cu, Ag and Zn ions cannot diffuse through amorphous structures as fast as through the crystalline counterpart structures and therefore their antimicrobial performance is lower. Among all materials Ti-based alloys have the potential to be applied as implants due to their good biocompatibility, high corrosion resistance and excellent mechanical properties. Control of the cooling rate enables to develop titanium alloys with different microstructures and performances [7], such as in Ti-6Al-4V alloys [8], Ti-5321 [9] and Ti-10Mo-1Fe [10] alloys.

This project will focus on Ti-3.5Cu [11], Ti-2Ag [12] and Ti-3.5Zn wt. % alloys since Cu, Ag and Zn are well-known antimicrobial elements and these concentrations are reported to be high enough to provide antimicrobial activity but without being cytotoxic.

Traditional alloy casting to make implants needs subsequent complex heat treatments to achieve the microstructure and therefore the performance desired. Rapid solidification, however, is inherently a departure from the traditional approach, since it enables to achieve the optimum microstructure directly upon quenching (i.e., in one single step) without the need of heat treatments and therefore represents an exciting paradigm shift. This will potentially open up exciting new possibilities for other researchers to apply to other alloy systems and will demonstrate the effectiveness of our Ti-based alloys that will open new avenues of enquiry across the wider Materials Science community and beyond.

Preliminary data: We have evidence that harnessing rapid solidification enables to develop novel metallic alloys with optimum mechanical and antimicrobial performance (see thesis of Sergio’s ex-PhD student, Victor Manuel Villapún Puzas (see file attached). The research was done for CuZr alloys, now this project aims to explore a different system by focusing on titanium-based alloys.

References:

[1]   S. Gonzalez et al. J. Mech. Behav. Biomed. Mater. 6 (2012) 53.

[2]   J. Fornell, S. González et al. J. Alloys Compd. 536S (2012) S74.

[3]   E. Pellicer, S. González et al. J. Biomed. Mater. Research Part A, 101A (2013) 502.

[4]   Villapún et al. Materials and Design 115 (2017) 93.

[5]   Villapún et al. Materials 10 (2017) 506.

[6]   J. Black, G.W. Hastings, eds. Handbook of biomaterials properties. Chapman and Hall, London, UK, 1998.

[7]   C. Suryanarayana, F.H. Froes et al. Inter. Materials Reviews 36 (2023) 85.

[8]   A. Shaikh, S. Kumar, et al. Procedia Structural Integrity 14 (2019) 782.

[9]   C. Wu, Y. Zhao et al. J. Alloys Compds. 841 (2020) 155728.

[10] B. Gao, Q. Wang et al. J. Mater. Research and Tech. 23 (2023) 5221.

[11] M. Bao, Y. Liu et al. Bioactive Mat. 3 (2018) 28)

[12] S. Maharubin, Y. Hu et al. Mater Sci Eng C 105 (2019) 110059.

Section 5 - Plan of investigation

Plan of investigation:

List of abbreviations: SG: Sergio Gonzalez (@Northumbria, NU); NJ: Nick Jakubovics (@Newcastle, UoN), DD: David Deehan & MM: Martin Marsh (@ Freeman hospital Newcastle). DS: David Simpson (@Adler Ortho UK Ltd.), PDRA: Postdoctoral research associate

We will hold an on-line meetings, 4 in 1 year, starting with a kick-off meeting with participation of all the members (SG, NJ, DD, MM, DS &PDRA).

1) WP1(SG & PDRA@NU) (5 months): to produce samples of different microstructures through control of the cooling rate (casted samples of 2, 3 and 6 mm diametre). This approach was proven by us to be effective for performance control [1].

T.1.1. To suction cast all the Ti-based alloys of different diameters with chiller on.

T.1.2. To suction cast all the Ti-based alloys of different diameters with chiller off.

2) WP2(SG & PDRA@NU) (4 months): Microstructural characterization and mechanical performance of the as-cast samples of WP1.

T.2.1. Microscopy analysis (SEM-EDX) of the samples of T.1.1. and T.1.2.

T.2.2. Wear and compression tests of the samples of T.1.1. and T.1.2.

3) WP3 (NJ & PDRA@UoN) (6 months): Biological performance of the as-cast samples of WP1 using strains of clinically relevant pathogens: Acinetobacter baumanii, Escherichia coli and Staphylococcus aureus.

T.3.1. Antimicrobial behaviour of the samples of WP1 will be analysed and quantified by counting the number of Colony Forming Units.

T.3.2. Biofilm formation and antimicrobial behaviour of the samples of WP1 will be analysed and quantified by microscopy.

 

Reference:

[1] V.M. Villapún, F. Esat, S. Bull, L.G. Dover, S. González. Materials 10 (2017) 506.

Section 6 - Research environment and resources

Research environment and resources:

Northumbria Univ. will provide laboratory space and access to the PDRA to our facilities. This includes a melting fabrication technique consisting of a suction casting arc melter, which enables cooling rate control by using a chiller and different coper mould diameters. The mechanical test facilities include an Instron to perform compression tests at room temperature at different loading rates to obtain the strength of the metallic alloys. A pin-on-disc is available a few metres from the equipment used to make the samples, which enables wear tests up to 70 Kg load to assess the durability of the alloys. In addition, we have a Scanning Electron Microscope (SEM) with EDX for compositional analysis and an X-rays to identify the crystalline phases of the metallic alloys.

The Translational Oral Biosciences laboratory in Newcastle University School of Dental Sciences is a containment level 2 facility fully equipped for microbiology and molecular biology research. The PDRA will be allocated bench space and will be provided with the necessary induction and training. Access to scanning electron microscopy for biofilm analysis is available within a short walk at the Electron Microscopy Research Services unit. We have an extensive microbial culture collection that includes strains harvested from prosthetic joint infections in previous projects. In addition, we can collect new strains from the Orthopedics Department or the clinical microbiology laboratories at the Freeman Hospital, Newcastle-upon-Tyne. The laboratory has three technicians including a research technician who has previously worked with a range of students and post-doctoral researchers on projects at the interface of materials science and microbiology.

The PDRA will have the opportunity to develop multidisciplinary skills in metallurgy and in microbiology and to learn about implant technology by liaising with Adler Ortho via our regular Skype meetings through their in-kind contribution in the form of staff time.

In addition, we will promote professional development and experience in orthopaedic challenges of patients with MSK conditions through their contact with orthopaedic clinicians Prof. Deehan and Dr. Marsh (attendance at quarterly meetings).

In addition, the PDRA will lead a PPIE event with a panel of patients from the existing PPIE panels of musculoskeletal/orthopaedics patients to learn about their health challenges to incorporate this knowledge into a follow-on proposal.  The PDRA will be also participate in outreach activities in Newcastle such as “A pint of science” to disseminate the knowledge gained from this project.

Section 7: Research impact

Who will benefit from this research?

Patients with MSK conditions will benefit through the Newcastle upon Tyne Hospitals, where the consultant orthopaedic surgeons Prof. Deehan and Dr. Martin Marsh will provide advice. The burden on NHS will be reduced through the Research and Development Department of the NHS Foundation Trust by putting into practice the research findings of this project to reduce infection costs and revision surgery.

The outcomes and knowledge sharing meetings with the company AdlerOrtho, will be useful for them to provide better products to patients, which will ultimately increase revenue and therefore job opportunities.

We will promote educational Programmes for the general population by running one Patient and Public Involvement (PPIE) event at the end of the project where families will have access to a relevant group through the Newcastle BRC. To receive feedback about what they have learnt and what to improve, participants will be given a short questionnaire at the end.

How can your research be translated in real-life?

This research will be translated in real-life through the support of Mr. David Simpson (Group Programme Director – Limb Salvage and Oncology) from Adler Ortho UK Ltd., who will help translate the knowledge and findings of this project into usable orthopaedic implants via 3D printing, a near net-shape technology that produces products highly dependent of the solidification rate of the alloy.

Customised designs for the patients as well as clinical trials will be proposed from the extensive experience of Prof. Deehan and Dr. Martin Marsh, consultant orthopaedic surgeons from the Newcastle upon Tyne Hospitals. In addition, they will support implementation of the implants by linking the project with NHS Foundation Trust through their Research and Development Department. This project will support their workforce whose culture and behaviours demonstrate the value of research in improving patient care.

How will your research be beneficial for ORUK and its purpose?

Since the pandemic, waiting lists for elective orthopaedic surgery have reached record levels. Complications from poor functioning prosthetic joints or prosthetic joint infections increase the burden on individual patients and on the healthcare system as a whole. Rapid solidification technology is an innovative approach to develop novel microstructures to achieve high performance implants. By assembling a team of basic scientists, clinicians and industrial advisor, we will be well-placed to develop the most successful approaches towards clinical application. Improvements in the strength, durability and infection resistance of prosthetic joints would provide significant benefits to musculoskeletal health across the population, a key goal of ORUK. As added value, this technology has the potential to open up exciting new possibilities for other researchers to apply to other alloy systems across the wider biomaterials community and beyond.

Section 8: Outreach and engagement

We will continually look for opportunities to enhance the impact of our research through engagement with the public throughout the project. In addition, we have allocated time for specific engagement events. For example, we will involve patients in helping steer the next phase of the project through a PPIE panel meeting at the RVI hospital in Newcastle. This will provide guidance for the further development of materials and will help us to understand the needs of the patient group as we move forward with the next steps towards translation.
We have a track record of engagement, for example through outreach to schools and showcasing our work at events such as ‘Science City’. As part of this project, the PDRF will participate in a public engagement event such as “A Pint of Science” or “Soapbox Science” in Newcastle upon Tyne. A Pint of Science is a popular event that brings researchers to the local pub or café to share their scientific discoveries with the general public. Soapbox Science is aimed at promoting women and non-binary scientists and showcasing the work they do. Events like these help to build UK public’s appreciation of science and combats negative stereotypes within the science sector and champions excellence in the UK science sector.
We will further promote the findings of the project through social media and press releases as appropriate. We have had extensive global media coverage of previous projects by working with our University press offices and we would look to disseminate novel findings with high potential for patient benefit through these channels.
In addition, we will help foster young kid’s curiosity in biomaterials and engage the next generation of citizens and scientists by writing an article for Frontiers for Young Minds (https://kids.frontiersin.org/).

Section 9: Research budget

Requested funding from ORUK

University fees (if any)
£0

Salary
£42995.22

Consumables
£2925

Publications
£0

Conference attendance
£0

Other items
£2574

Total 'requested fund'
£48494.22



Other items
Northumbria University SEM analysis - 1,200.00 Newcastle University SEM analysis - 1,121.00 PPIE – 253.00



Other secured funds

Internal funding
£0

Partner (University)
£0

Partner (Commercial)
£10000

Partner (Charity)
£0

Other sources
£0

Total 'other funds)
£10000

Section 10: Intellectual property and testing on animal

Is there an IP linked to this research?
No

Who owns and maintains this patent?


Does your research include procedures to be carried out on animals in the UK under the Animals (Scientific Procedures) Act?
No

If yes, have the following necessary approvals been given by:

The Home office(in relation to personal, project and establishment licences)?


Animal Welfare and Ethical Review Body?


Does your research involve the use of animals or animal tissue outside the UK?
No

Does the proposed research involve a protected species? (If yes, state which)



Does the proposed research involve genetically modified animals?


Include details of sample size calculations and statistical advice sought. Please use the ARRIVE guidelines when designing and describing your experiments.


There should be sufficient information to allow for a robust review of any applications involving animals. Further guidance is available from the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), including an online experimental design assistant to guide researchers through the design of animal experiments.

Please provide details of any moderate or severe procedures


Why is animal use necessary, are there any other possible approaches?


Why is the species/model to be used the most appropriate?