Understanding haemarthrosis in the ankle joint
Lead Research Organisation:
University of Leeds
Department Name: Mechanical Engineering
Abstract
Local bony defects within the ankle can be caused by a number of factors, including defects arising from bleeds into the ankle joint due to haemophilia, having a significant impact on the quality of life for the young male patients it affects.
These defects can affect the local contact mechanics and tribology, through changes in bony geometry and mechanical properties of the bone and cartilage tissues. Studies have suggested the potential for progression from such defects to arthritis of the ankle joint. End-stage treatment for ankle arthritis does not presently provide an adequate solution for the younger patients this degeneration typically affects.
Initial degeneration of the ankle joint is clearly a biological process, influenced by bleeds into the joint. These impact on the mechanical properties of both the cartilage and bone, resulting in defects and changes in ankle morphology. Development of appropriate biological and mechanical models to represent these defects, through in-vitro methods is critical in understanding the mechanism of degeneration in the ankle joint. By better understanding these changes there will be potential for identifying interventions to mitigate this degeneration pathway.
Development of ankle models to date has been limited due to the complexity of the biomechanics and the joint. However, there is a clear clinical need for the application of bioengineering techniques to this problem area. At the University of Leeds, a number of research projects have focussed on bony defects in the hip and knee, and there will be some translation of previous research to the ankle joint.
The specific research questions are as follows:
1. What effect does exposure to blood have on the histological and mechanical properties of bone and cartilage?
2. What are the changes observed in bony morphology, and how does this vary across the patient population?
3. What methods can we use to 'degrade' human ankle bone to create defect models representative of the haemoarthritic ankle?
The aim of this project is to understand the early stages of the degeneration pathway in the ankle relating to haemarthrosis, and to determine the transition from a biological to a primarily mechanical failure mechanism
Objectives:
1. To identify the geometric changes in the ankle relating to bony defects
a. Identify typical 'normal' talar geometry
b. Identify changes in geometry relating:
i. Haemophilia related defects (typically joint surface geometry)
2. To identify changes in mechanical properties of the bone and cartilage following exposure to blood
a. Mechanical characterisation of tissues (where available)
b. Microscopic analysis - histology and immunohistochemistry
3. Development of representative defect models (using data from 1 & 2)
a. Investigation of methods for developing 'degraded bone'
i. Biochemical degeneration of cadaveric bone tissue
ii. 3D printing of talar models with representative defects and bony structure
iii. Computational FE models of the ankle joint
4. To investigate the effect of defects on the tribology of the ankle joint under a range of appropriate conditions(experimentally)
a. static loading (contact pressure e.g. Tekscan)
b. experimental testing in a natural joint simulator (fatigue, friction, wear)
- Characterisation of the geometry of the natural ankle
- Development of novel experimental methods focussed on the ankle joint
- Limited natural ankle modelling has been undertaken to date, and therefore this project represents a significant bioengineering advance in the ability to develop a model for predicting degeneration.
- Potential platform for future treatment development
These defects can affect the local contact mechanics and tribology, through changes in bony geometry and mechanical properties of the bone and cartilage tissues. Studies have suggested the potential for progression from such defects to arthritis of the ankle joint. End-stage treatment for ankle arthritis does not presently provide an adequate solution for the younger patients this degeneration typically affects.
Initial degeneration of the ankle joint is clearly a biological process, influenced by bleeds into the joint. These impact on the mechanical properties of both the cartilage and bone, resulting in defects and changes in ankle morphology. Development of appropriate biological and mechanical models to represent these defects, through in-vitro methods is critical in understanding the mechanism of degeneration in the ankle joint. By better understanding these changes there will be potential for identifying interventions to mitigate this degeneration pathway.
Development of ankle models to date has been limited due to the complexity of the biomechanics and the joint. However, there is a clear clinical need for the application of bioengineering techniques to this problem area. At the University of Leeds, a number of research projects have focussed on bony defects in the hip and knee, and there will be some translation of previous research to the ankle joint.
The specific research questions are as follows:
1. What effect does exposure to blood have on the histological and mechanical properties of bone and cartilage?
2. What are the changes observed in bony morphology, and how does this vary across the patient population?
3. What methods can we use to 'degrade' human ankle bone to create defect models representative of the haemoarthritic ankle?
The aim of this project is to understand the early stages of the degeneration pathway in the ankle relating to haemarthrosis, and to determine the transition from a biological to a primarily mechanical failure mechanism
Objectives:
1. To identify the geometric changes in the ankle relating to bony defects
a. Identify typical 'normal' talar geometry
b. Identify changes in geometry relating:
i. Haemophilia related defects (typically joint surface geometry)
2. To identify changes in mechanical properties of the bone and cartilage following exposure to blood
a. Mechanical characterisation of tissues (where available)
b. Microscopic analysis - histology and immunohistochemistry
3. Development of representative defect models (using data from 1 & 2)
a. Investigation of methods for developing 'degraded bone'
i. Biochemical degeneration of cadaveric bone tissue
ii. 3D printing of talar models with representative defects and bony structure
iii. Computational FE models of the ankle joint
4. To investigate the effect of defects on the tribology of the ankle joint under a range of appropriate conditions(experimentally)
a. static loading (contact pressure e.g. Tekscan)
b. experimental testing in a natural joint simulator (fatigue, friction, wear)
- Characterisation of the geometry of the natural ankle
- Development of novel experimental methods focussed on the ankle joint
- Limited natural ankle modelling has been undertaken to date, and therefore this project represents a significant bioengineering advance in the ability to develop a model for predicting degeneration.
- Potential platform for future treatment development
Planned Impact
Regenerative Medicine been defined as "an interdisciplinary approach, spanning tissue
engineering, stem cell biology, gene therapy, cellular therapeutics, biomaterials (scaffolds and matrices),nanoscience, bioengineering and chemical biology that seeks to repair or replace damaged or diseased human cells or tissues to restore normal function, (UK Strategy for Regenerative Medicine). CDT TERM will focus on acellular therapies, scaffolds,autologous cells and regenerative devices, which can be delivered to patients as class three device interventions, thus reducing the time and cost of translation and which provide an opportunity to deliver economic growth and benefits to health in the next decade. The primary beneficiaries of CDT TERM are patients, the health service, UK industry, as well as the academic community and the students themselves. Recognising that the impact and benefit from CDT TERM will arise in the future, the statements describing impact below are supported by evidence of actual impact from our existing research and training.
Patients will benefit from regenerative interventions, which address unmet clinical needs, have improved safety and reliability, have been stratified to meet patients needs and manufactured in a cost effective manner. An example of impact arising from previous students work is a new acellular scaffold for young adult heart valve repair, which has demonstrated improved clinical outcomes at five years.
The Health Service will benefit from collaborations on research, development and evaluation of technologies, through existing partnerships with National Health Service Blood and Transplant NHSBT and the Leeds Biomedical Musculoskeletal Research Unit LMBRU. NHSBT will benefit through collaborative projects, through technology transfer, through enhancement of manufacturing processes, through pre-clinical evaluation of products and supply of trained personnel. We currently collaborate on heart valves, skin, ligaments and arteries, have licensed patents on acellular bioprocesses, and support product and process developments with pre-clinical testing and simulation. LMBRU and NHS clinicians will benefits from our collaborative research and training environment and access to our research expertise, facilities and students. Existing collaborative projects include, delivery devices for minimally manipulated stem cells and applied imaging for early OA.
Industry will benefit from supply of highly trained multidisciplinary engineers and scientists, from collaborative research and development projects, from creation and translation of IP, creation of spinout companies and through access to unique equipment, facilities and expertise. We have demonstrated: successful spin outs in form of Tissue Regenix and Credentis; successful commercialisation of a novel biological scaffolds for vascular patch repair; sustainable long term R and D and successful licensing of technology with DePuy; collaborative research with Invibio, partnering with Simulation Solutions to develop new pre-clinical simulation systems, which been adopted by regulatory agencies such as China FDA. Our graduates and researchers are employed by our industry partners.
The academic community will benefit through collaborative research and access to our facilities. We have funded collaborations with over 30 academic institutions in UK and internationally. The CDT TERM will support these collaborations and the academic partners will support student research and training. The CDT students will benefit from enhanced integrated multidisciplinary training and research, a cohort experience focused on research innovation and translation, access to our research partners, industry and clinicians. Feedback from existing students has identified the benefit of the multidisciplinary experience, the depth and breadth of excellence in our research base, the outstanding facilities and the added value of the cohort training.
engineering, stem cell biology, gene therapy, cellular therapeutics, biomaterials (scaffolds and matrices),nanoscience, bioengineering and chemical biology that seeks to repair or replace damaged or diseased human cells or tissues to restore normal function, (UK Strategy for Regenerative Medicine). CDT TERM will focus on acellular therapies, scaffolds,autologous cells and regenerative devices, which can be delivered to patients as class three device interventions, thus reducing the time and cost of translation and which provide an opportunity to deliver economic growth and benefits to health in the next decade. The primary beneficiaries of CDT TERM are patients, the health service, UK industry, as well as the academic community and the students themselves. Recognising that the impact and benefit from CDT TERM will arise in the future, the statements describing impact below are supported by evidence of actual impact from our existing research and training.
Patients will benefit from regenerative interventions, which address unmet clinical needs, have improved safety and reliability, have been stratified to meet patients needs and manufactured in a cost effective manner. An example of impact arising from previous students work is a new acellular scaffold for young adult heart valve repair, which has demonstrated improved clinical outcomes at five years.
The Health Service will benefit from collaborations on research, development and evaluation of technologies, through existing partnerships with National Health Service Blood and Transplant NHSBT and the Leeds Biomedical Musculoskeletal Research Unit LMBRU. NHSBT will benefit through collaborative projects, through technology transfer, through enhancement of manufacturing processes, through pre-clinical evaluation of products and supply of trained personnel. We currently collaborate on heart valves, skin, ligaments and arteries, have licensed patents on acellular bioprocesses, and support product and process developments with pre-clinical testing and simulation. LMBRU and NHS clinicians will benefits from our collaborative research and training environment and access to our research expertise, facilities and students. Existing collaborative projects include, delivery devices for minimally manipulated stem cells and applied imaging for early OA.
Industry will benefit from supply of highly trained multidisciplinary engineers and scientists, from collaborative research and development projects, from creation and translation of IP, creation of spinout companies and through access to unique equipment, facilities and expertise. We have demonstrated: successful spin outs in form of Tissue Regenix and Credentis; successful commercialisation of a novel biological scaffolds for vascular patch repair; sustainable long term R and D and successful licensing of technology with DePuy; collaborative research with Invibio, partnering with Simulation Solutions to develop new pre-clinical simulation systems, which been adopted by regulatory agencies such as China FDA. Our graduates and researchers are employed by our industry partners.
The academic community will benefit through collaborative research and access to our facilities. We have funded collaborations with over 30 academic institutions in UK and internationally. The CDT TERM will support these collaborations and the academic partners will support student research and training. The CDT students will benefit from enhanced integrated multidisciplinary training and research, a cohort experience focused on research innovation and translation, access to our research partners, industry and clinicians. Feedback from existing students has identified the benefit of the multidisciplinary experience, the depth and breadth of excellence in our research base, the outstanding facilities and the added value of the cohort training.
Organisations
People |
ORCID iD |
| Claire Brockett (Primary Supervisor) | |
| Megan Sharrock (Student) |
| Description | A proposed pathway of what happens within a synovial joint during a bleed has been created to show how haemarthrosis occurs, Existing literature demonstrated independent mechanisms whereas this proposed pathway depicts multiple mechanisms at play synergistically. These include the effects of both reversible indirect synovitis and irreversible cartilage damage. The four main pathways of importance include synovial inflammation, macrophage-mediated inflammation, cartilage degradation and downstream effects on the subchondral bone. Focusing on damage to articular cartilage, conditions to mimic a joint bleed in vitro used blood and serum (synovial fluid proxy) throughout mechanical testing. It was found that exposure to blood reduced friction and deformation on the articular surface. However, mixed exposure and lubricant fluids of both blood and serum increased friction and deformation on the articular surface. This condition is the most clinically relevant as synovial fluid is mixed with blood during haemorrhage within synovial joints. |
| Exploitation Route | By producing a complete proposed pathway of haemarthrosis future research can hone in on particular areas of the cascade to allow for more specific testing. This can help to improve current diagnostic techniques and create specific treatments for haemarthrosis. It will also allow others to determine which areas of the pathway require more attention. For example, my research is focused on irreversible cartilage damage as synovial inflammation can be reversed and extensive research already exists through previous literature on rheumatoid arthritis that has similar mechanisms at play. The mechanical testing that has been completed provides clinically relevant information. This includes the type of mechanical stress that occurs in haemarthritic joints, number of bleeds required to cause damage and extent of damage per bleed such as deformation, wear and staining. |
| Sectors | Healthcare |