Biomechanical evaluation of subchondroplasty

Osteoarthritis (OA) is one of the leading causes of pain and disability, affecting upwards of 10% of UK adults and growing more prevalent in our ageing and increasingly obese population. Damage to the subchondral bone (termed a bone marrow lesion (BML)) is associated with both OA symptoms and structural progression. However, there are no licensed treatments to repair bone damage in OA.
Vertebroplasty has been used in the treatment of vertebral compression fractures for some time and provides an analogous model for treating damaged and microfractured bone. Here, cement is injected into the fracture site with the aim of stabilising the fracture and preventing further height loss of the vertebra. So could a similar approach be used to treat knee OA patients with subchondral bone damage?

There are currently very limited experimental data examining potential subchondral interventions (or 'subchondroplasty') in the knee. One study of 25 patients found a significant reduction in pain at 6-24 months post percutaneous calcium phosphate injection, although 45% of patients had a poor clinical outcome. A further case study reported BML resolution and pain reduction 31 months after percutaneous calcium phosphate injection. These studies provide proof-of-concept that subchondral therapy of the knee is viable, however no biomechanical assessment of the therapy has been undertaken and further work is required to identify the ideal material for treatment of subchondral bone damage in knee OA.

The major research challenges are in the development of experimental and computational models to evaluate the biomechanical efficacy of subchondroplasty.
The study will involve close collaboration between engineering and medicine. The clinical BML evidence must be interpreted to develop a biomechanical model, the treatments investigated must be clinically feasible and indications based on the data available from patient imaging.

Early-stage treatment to prevent or delay the progression of OA remains a major unmet clinical need. This study will provide the underpinning biomechanical information on the effects of subchondroplasty. Parallel clinical studies are also planned and the combined evidence will help determine if subchondroplasty can provide an effective treatment for early-stage OA. If the outcomes are positive, then this biomechanical study will also help identify the subsets of patients who would benefit, and important clinical indicators for its future use.

The aim of this study is to investigate whether local BML treatment with injectable biomaterials could provide a treatment in knee OA patients with subchondral bone damage.
The major objectives are:
1. To develop computational (finite element) models of the knee to examine the joint contact mechanics and how this is compromised by differing sizes and positions of bone marrow lesions. There is a large body of clinical image data to support the development of the models, and image analysis/processing could play a major role in developing the models.
2. To use the models to assess the subchondroplasty procedure and whether this it is able to restore mechanical and tribological function, examining a range of different treatment and patient variables.
3. To develop parallel in vitro experimental models that can be used to validate the computer models and test the clinical feasibility of the procedures investigated
The computational modelling will make use of the extensive expertise and computational facilities available within the IMBE. The group has previously developed the first biphasic whole-joint FE models to examine cartilage contact mechanics as well as validated methods of representing bone augmentation in vertebroplasty. The project will make use of state-of-art software (FEBio, Abaqus, Simpleware) and hardware including the university's high performance computing facilities.

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.