FP-00036

Section 1 - Basic information about you and your application:

Title of research project
Developing a novel algorithm to predict the risk of metal-on-polyethylene joint replacement failure

Grant Type
The Ronald Furlong Fund

Research area
Diagnostic

Duration
2 years

Start date
March 1, 2024

Have you previously received funding from ORUK?
No.

Profession
Entrepreneur

Your current job title/position
Director and Chief Scientific Officer

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

Section 2 - Lay summary

Lay summary:

As people get older, their joints such as their knee, hip, ankle, elbow and shoulder are subjected to ongoing wear and tear. Similar to how cars require part replacements with increased mileage, damaged human joints can be replaced when needed. Osteoarthritis, the most prevalent arthritis type in the UK, leads to sore and stiff joints, often necessitating joint replacements. Surgeons have various replacement joints at their disposal, including ones crafted from metal and plastic components. While many receive these implants without discomfort, some experience immune responses, leading to pain and eventual joint replacement failure. When this happens, the patient often has to go back into the hospital to get the implant taken out and replaced with another type of implant. Having a second operation, so-called revision surgery is not ideal. It causes the patient more hassle and costs the NHS more money. Our aim is to prevent such occurrences, enabling patients to maintain pain-free, active lives and avoiding the need for major, potentially life-threatening replacement surgeries.

Over 200,000 NHS patients undergo knee, hip, ankle, elbow, and shoulder arthroplasty surgeries annually in England and Wales. Unfortunately, some of these surgeries fail, necessitating costly and complex ‘revision surgery.’ This secondary procedure poses higher risks of severe complications like bleeding, infection, and dislocation. Recent global data from countries including the United States, Spain, Portugal, the Netherlands, Canada, France, Italy, Switzerland, Germany, Romania, Denmark, England and Wales, Sweden, Norway, and Australia revealed an estimated 959,000 total hip procedures yearly, combining primary and revision surgeries. The average rate of total hip arthroplasty stood at 131 procedures per 100,000 population, with an average revision burden of 12.9%. Notably, 57.7% of patients were women, and 32.9% were under 65 years old.

Patients with MSK conditions, particularly those who have undergone joint replacement surgeries, will be invited to participate voluntarily in our study.Our research is going to investigate if people’s genetics can be looked at before they have surgery to determine if they are more or less likely to have a bad reaction to metal and plastic implants. What this means is that for people with osteoarthritis who are going to need to have joint replacement surgery, the output of this research will help to determine if metal and plastic implants are a safe option for their replacement joints.If it looks like it isn’t, a different type of implant can be chosen, and this should help improve the success of the implants over the long term. This will give better outcomes to the patient. There are a range of other different musculoskeletal conditions where implants are used to help correct or fix the problem. This research will be helpful for anyone who needs to undergo an implant procedure.

Section 3 - Purpose of research

Purpose of research:

BACKGROUND: Using the bespoke, validated methodology, our laboratory can accurately quantify and map the volumetric wear of explanted joint replacement prostheses (knee, hip, ankle, elbow, and shoulder ). We correlate these results to the host’s immune response. The immune response is critical to the clinical success of an implant. However, this response, certainly from a genetic stance, is poorly understood. In 2019, we were awarded the British Hip Society prize for research in which we stratified patients according to the volumetric wear rates of their explanted metal-on-metal hip replacements and identified genes associated with early failure of their devices. To date, scant research has examined the influence of immunogenetics on a patient’s propensity to develop osteolysis following implantation with a metal-on-polyethylene(MoP) joint replacement prostheses. With ORUK’s help, we would like to address this gap.
AIM: Conduct primary research enabling us to develop a new algorithm to predict patient reaction to, and failure of, MoP implants. This would enable: (i) personalised joint replacement guided by an individual’s genetically determined reactivity to specific compounds, thus improving patient outcomes; (ii) monitoring of patients already implanted with MoP prostheses.
OBJECTIVES: (i) Audit and expand the existing database of explanted prostheses to identify patients with MoP joint failures who have been exposed to different volumes of wear. (ii) Send DNA collection kits to these patients to collect buccal swabs (iii) Perform next-generation sequencing on the samples, specifically for high-resolution typing of HLA Class I and II alleles. (iv) Investigate statistical associations of HLA alleles and other clinical variables influencing device failure and build statistical models to interpret the multiple data parameters (v) Develop a predictive algorithm.
DELIVERABLES: (i) An algorithm capable of predicting immune response to MoP implants, and deliver a risk score for potential future rejection/failure of MoP implant.

Section 4 - Background to investigation

Background to investigation:

Orthopaedic joint replacements are recognised as cost-effective surgeries, offering reliable pain relief and improved quality of life. Polyethylene (PE), ultra-high-molecular-weight polyethylene (UHMWPE), highly cross-linked polyethylene (HXLPE), and vitamin E enriched PE are frequently used in metal-on-polyethylene (MoP) joint replacements.

The long-term survival of a prosthesis is determined to a large extent by the host immune response to debris which is shed from the components. The more a replacement joint is used (the more active the patient), the higher the volume of wear debris that is generated. The main failure mechanism of total joint arthroplasty with MoP articulations is aseptic implant loosening. Here, it has been found that PE wear particles migrate within the entire periprosthetic bed, known as “the effective joint space”. Interaction with the local cells (resident phagocytic macrophages, osteoblasts, and osteoclasts) triggers a cascade of proinflammatory responses. This inflammatory cascade leads to the release of various proinflammatory cytokines (IL-1, IL-6, TNF-α), growth factors (macrophage colony-stimulating factor-1) and chemokines (MIP-1α, MCP-1), and can result in PE-induced osteolysis (Gibon et al.,2017).

Polyethylene-induced osteolysis is the process by which prosthetic debris is mechanically released from the surface of prosthetic joints, and induces an immune response that favours bone catabolism, resulting in loosening of prostheses. This the main mechanism which limits the lifespan of a MoP joint replacement prosthesis.
It is well recognised that humans are living longer and becoming increasingly obese. This means that the likelihood of patients outliving their joint replacements is increasing. It is generally accepted that the rates of revision surgery will increase globally. Research on the immune characteristics of individual patients has not, as yet, been forthcoming. Currently, a “one size fits all” approach exists for implant selection and follow up post-surgery.
Two genome-wide association studies were conducted to identify genetic risk loci associated with osteolysis and genetic risk loci associated with time to prosthesis failure due to osteolysis (Wilkinson et al.,2018). Five independent genetic signals showed a suggestive association. However, they did not account for volumetric wear in their analysis.
We and others have conducted research that shows that HLA Class II DRB1, DQA1, and DQB1 alleles exert either a protective or predisposing influence in the development of adverse reaction to metal debris (ARMD) causing failed MoM implants. For example, it has been shown that HLA-DQA1*05 is present at increased frequency in failed metal-on-metal (MoM) patients, while HLA-DRB1*15, -DQA1*01:02 and – DQB1*06 are decreased in failed implant groups, suggesting a “protective” effect (Blowers,2015).
The shape of the peptide-binding groove of macrophages and other antigen-presenting cells are dictated by the major histocompatibility complex (MHC), genes. Our own protein modelling work has shown how specific MHC genes (HLA DQA1 and DQB1 alleles) are more suited to binding the N-terminal peptide fragments of albumin – and patients with these genotypes are significantly more likely to develop dysregulated immune responses to MoM implants. We examined over 400 explanted MoM hips, see Figure 1. We have found that certain HLA genes (specific for male and females) provide a greater explanation for the observed rates of ALVAL. Using regression statistical modelling, with patient age and sex as variables included, we have invented algorithmic means to estimate a patient’s relative risk of developing ARMD. Furthermore, preliminary results of 100 explanted MoP total knee replacements from our lab are shown in Figure 2. It can be seen that there is a suggestion that MoP osteolysis may be influenced by the same factors leading to the development of ALVAL in MoM hips.
To our knowledge, no previous studies have examined the influence of metal and PE volumetric wear, a patient’s immunogenetics and their propensity to develop osteolysis following implantation with MoP joint replacement prostheses (knee, hip, ankle, elbow, and shoulder ). With ORUK’s help, we would like to do this via this research project.
We plan to conduct research towards developing a predictive algorithm that can be used:
(i) post-operatively for advising follow up strategy: identifying genes associated with early failure or long-term survival of joints may allow clinicians to increase or reduce the intensity of post-operative surveillance protocols as appropriate.
(ii) pre-operatively to guide implant selection: this will enable patients requiring primary joint replacement surgery to have an implant chosen based on individual diagnostics, offering the best potential outcome and therefore hopefully improved implant longevity.
The ability to identify “at-risk” patients through preoperative screening affords the potential opportunity to avoid the morbid sequelae resultant from revision arthroplasty.
HLA genes (specifically the class II genes DQA1/DQB1) can be collected using non-invasive methods, such as from a cheek (buccal) swab.
Such studies can only be carried out following quantification of the “dose exposure,” i.e. the amount of wear a patient has been exposed to. As the only independent facility of its kind, we are in a unique position to carry out such a study.
We believe that an improved understanding of individual variations in the immune response to particles will have a far-reaching, positive global impact. Prior research published in other clinical areas suggests that the research outcomes may have significant implications for other immune modulated musculoskeletal (MSK) conditions (such as rheumatoid arthritis) where involvement of HLA haplotypes is strongly suspected.
State-of-the-art: Assessing patients for their likely responses to MoP implants based on their individual HLA-haplotypes is not part of the existing patient care pathway. This project will pave the way for a step-change in pre and post-operative patient care of patients requiring MoP implants and will lead to fewer premature joint failures in the future, improve overall patient outcomes, and save the NHS money.

(Note: Figure1 and 2 are attached in a separate pdf file)

Section 5 - Plan of investigation

Plan of investigation:

WP1: Project Management

1.1 Ongoing technical and financial project management using project management toolkit. Tools used to monitor project progress include: Project Timing Plan; A Risk Register; A detailed project schedule; A Change Log; An Action Tracker; Budgeted Cost of Work Scheduled; Actual Cost of Work Performed; Budgeted Cost of Work Performed; Cost Variance; Cost Performance Index; Overdue Project Tasks/Crossed Deadlines; Schedule Variance; Schedule Performance Index; Percentage of Tasks Completed; Resource Utilisation.

Milestones: Quarterly Project Review Meetings

Deliverable: Final project report

 

WP2: System Specification

2.1. Review current guidelines used to assess risk prior to implantation

2.2. Develop a technical specification for the algorithm to generate a risk profile

Milestone: Research completed

Deliverable: Specification for algorithm

 

WP3: Curation of New MoP data sets

3.1 Send 500 explant collection packs to X hospitals to collect explanted MoP joints.

3.2 Scan newly collected explants and analyse to confirm the volumetric wear rates of joint replacements that were revised secondary to osteolysis.

3.3 Send 25 patients identified as being in ‘high wear’ and 25 patients identified as being in ‘low wear’ groups buccal swab collection kits.

3.4 Identify a further 300 MoP patients with varying degrees of wear between ‘low’ and high’ and send buccal swab kits.

3.5 Process samples and send for full Class I and Class II MHC genotyping at the NHS Blood and Transfusion Service laboratories. This uses next-generation sequencing for six-digit resolution.

Milestone: 500 new explants collected

Milestone: 350 buccal swabs collected

Deliverable: Full MHC Class I and II profiling for 50 patients

 

WP4: Genetic Analysis

4.1: Compare Class I and II MHC allelic frequencies between the ‘high’ and ‘low’ wear groups.

4.2 Using targeted gene testing, obtain buccal swabs from a further 100 patients with failed joints identified in the explant cohort (collected in WP3.1), across a range of wear rates.

4.3 Compare the MHC haplotype results from patients with failed joints to the DNA of 150 patients who are asymptomatic at >10 years post-implant (identified from local hospital records).

Milestone: Identification of any statistically significant variance between MHC haplotypes in ‘high’ and ‘low’ wear groups. Our hypothesis is that the DQA1/DQB1 haplotypes will be the most significantly different.

Deliverable: Statistical reports.

WP5: Algorithm Development

5.1 Review published literature and proprietary research to delineate statistical relevance for clinical variables associated with the development of osteolysis

Milestone: Literature review completed

5.2 Build and test statistical regression models using multivariate logistic regression models. C-statistics, the Brier Score, and the Hosmer-Lemeshow chi-square test used to assess discrimination and calibration of the final multivariate model.

5.3 Programme algorithm using data variables and statistical methodology and train using data collected.

Milestone: Algorithm ready for validation in a subsequent clinical trial.

WP6: Exploitation planning

6.1 Clinical Pathway Mapping

6.2 Market access strategy planning (value proposition development, preliminary health economic analysis, technology appraisal and other forms of support for implementation into the NHS and other healthcare providers.

6.3 Ongoing IP review / landscaping

6.4 Technical file management; alignment of software/algorithm development plan with regulatory requirements.

6.5 Business strategy development. Assessment of potential licencing models and selected EU/ROW healthcare regulatory and reimbursement frameworks to support export sales

6.6 Market access and preliminary Health Economic modelling

Milestone: IP Assessment

Deliverable: Technical File

Deliverable: Detailed Business/Commercialisation Plan

Deliverable: Market Access & Health Economics Report

We have all technology in place, ethics approvals and have an established study protocol.

 

Throughout the project, we will maintain an active public dissemination process (described later).

 

Clinical experts (orthopaedic surgeons) and human genetics experts from a local university and NHS Trust will also support our research.

 

(Note: Please see attached Gantt chart.)

Section 6 - Research environment and resources

Research environment and resources:

Our laboratory is an independent research organisation focused on improving the performance of joint replacements to enhance the quality of patients’ lives. We were incorporated in 2011 to investigate failed orthopaedic devices (“explants”) to discover the cause of their failure, and have been operating as an independent research facility since then. As such, we do not have the requirement to operate through a technology transfer office.

 

We are already research and commercially active. We have a proven track record, with over forty published scientific papers in quality orthopaedic journals. Our laboratory currently provides a scanning service to NHS and other healthcare providers to assess the damage on explanted devices. As such, we have an income stream that de-risks the project – should more resources be required to ensure that the project completes on time, we have the funds to support additional activity. As our laboratory already supply services into the NHS, as well as providing medicolegal expert opinion, we already have an established network into which we can commercialise the outputs of this project.

Research Laboratory Facilities:
– Mitutoyo Legex 322 and Mitutoyo Strato 574 machines to scan the explants (hips and knees), which are then analysed using bespoke Matlab (Mathworks) software to produce volumetric and linear wear measurements as well as wear mapping.

– Ready access to computers and Microsoft Office software needed to co-ordinate explant collection and genotyping submissions to NHSBT.

– 95 sq metres

Fitted laboratory specification:

Category II:
– Laboratory benches, shelving and moveable under-bench storage
– Laboratory sinks and taps
– Climate control
– Fume cupboards with 1.2m and 1.8m external width, 0.9m deep with an extract volume flow rate of 0.35m3/s
– Fume cupboards with cold water, drip-cup and electrical power supply
– Gas bottle storage areas (bottles, pipework, regulator outlets for tenant to provide to their individual requirements)
– Independent electricity metering
– Secure/lockable door-entry system
– Anti-slip vinyl flooring to lab
– Carpet tile to write up
– Multiple power and data outlets
– Controlled LED lighting
– Mechanically ventilated
– Labs maintain negative pressure

Lab support:
– Postdoctoral researcher
– Senior Clinican technician
– Biomedical Engineer
– Senior Data Scientist
– Full on-site building staff
– 24/7 estate security
– Reception staff

Other relevant equipment:
– XRF GOLD++ alloy identifier

Section 7: Research impact

Who will benefit from this research?


How can your research be translated in real-life?

ExplantLab has already demonstrated its ability to translate its research into real world applications. In 2022 our research paper, “The influence of HLA genotype on the development of metal hypersensitivity following joint replacement”, was published in Nature Medicine. Through this research we identified that patient hypersensitivity reactions to cobalt chrome is higher risk in individuals with a specific genotype, and created a precision genetic test  to predict the potential for joint failure in these individuals. The test has been patented globally and is registered with the UK MHRA. The test is available to UK surgeons through NHSBT, a leading provider of genetic tests to the NHS. This grant will enable us to use the same successful model to also investigate potential sensitivity to polyethylene (a very common non-metal component in orthopaedic implants) and create a similar a precision diagnostic test to benefit clinicians and their patients.  

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

ORUK seeks to bring together musculoskeletal professionals to reach a common goal, “a healthy ageing society.”

We believe that our goals at ExplantLab are aligned with ORUK. We support clinical decision making in orthopaedics through our pioneering explant analysis and next-generation precision patient diagnostics. Our ultimate aim is to help improve the performance of orthopaedic implants so that patients have access to well performing, long lasting implants that provide years of pain free mobility and independence.  

Section 8: Outreach and engagement

Dissemination Plan
Throughout the study, we will engage with specialists and non-specialists alike through our laboratory website and associated social media channels (Twitter, Facebook, and LinkedIn business pages already established). Additionally, during the project, we will make every effort to engage the public via the following mechanisms:
1. Send out (every six months) copies of a study newsletter to participating hospitals, summarising progress to date, and encouraging patients to take part.
2. Create and host podcasts describing the project and progress to date, and advertise this on various social media channels.
3. Describe the ongoing research in personal blogs.
We will host copies of the newsletter and podcasts on our bespoke laboratory website and also upload them (or links to them) on public platforms including LinkedIn, Facebook and Twitter.
Once the research is complete, we will use the following dissemination methods to share the results of the study:
1. A press release timed to coincide with the official journal publication of our results.
2. A ‘Plain English’ Research Summary document understandable to lay readers.
3. Creation of flyers, brochures, posters and layperson research briefs.
4. A ‘thank you’ letter to participants, sharing with them key findings in Plain English.
5. In-depth research summaries will be sent to relevant charities.
6. Hold a public seminar to discuss the results.
7. Attend patient conferences and meetings to present the results to patients.
We will work with members of the public to translate research findings into lay summaries suitable for a general audience. We will make the necessary changes to language and layout, including the use of ‘question and answer’ style layouts, the addition of a reference list of scientific terms, and the removal of specific words.
We will use simple graphics to help explain complex ideas where this is practical.

Section 9: Research budget

Requested funding from ORUK

University fees (if any)
£0

Salary
£76896

Consumables
£23104

Publications
£0

Conference attendance
£0

Other items
£

Total 'requested fund'
£100000



Other items




Other secured funds

Internal funding
£40000

Partner (University)
£0

Partner (Commercial)
£0

Partner (Charity)
£0

Other sources
£0

Total 'other funds)
£40000

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?