Advanced therapies for intervertebral disc repair

There are two major scientific challenges to address if the PEP-GAG gels are to be successfully translated to clinic.

Challenge 1: To develop methods to effectively visualise the location of the gel, and identify if/where it disperses to over a period of time.
In order to assess the long term efficacy of the treatment, it is necessary to be able to quantify the degree to which the gel disperses out of the nucleus over time, in both in vitro laboratory tests and in vivo. We have successfully used clinical radio-opaque agents to visualise the immediate location of the injected gel under x-ray/CT, but longer term, the agent and gel will not necessarily diffuse at the same rate. There have been some initial attempts to chemically bond markers to the gel, but further investigation is needed to examine if this affects their performance. Recent work has also examined the use of histological methods to identify the peptides which have shown some promise. In parallel, we are continuing to develop in vitro testing methods to examine the performance of the PEP-GAG gel under cyclic loading in the laboratory and have a planned in vivo study due to commence next year.
If successful methods for visualising the gel can be developed, then greater evidence can be generated on the efficacy of the treatment and its likely longevity. If the gel can be seen long-term in vivo, then this will also reassure clinicians on how patients could be monitored. These aspects are critical if the PEP-GAG gel is to be successfully commercialised and adopted.

Challenge 2: To identify the most suitable patient characteristics for the treatment to be successful and the optimum volume of PEP-GAG gel to inject.
Different levels of disc degeneration cause changes to both the annulus and nucleus of the disc, and it is not yet known what stage of degeneration the treatment would be most effective, or what the important contra-indications would be. Our early laboratory findings have shown variance from specimen-to-specimen, likely due to the differences in the volumes of PEP-GAG injected compared to the degree of degeneration. Due to the large number of unknowns, this challenge is best addressed using computational models in which different variables can be systematically altered to evaluate their effect. We have developed finite element (FE) models of the disc to assess the mechanical performance, but the models do not yet have the sufficient sophistication in terms of representing the biphasic behaviour and gel-disc interactions to fully answer these questions.
Addressing this challenge will provide underpinning evidence necessary for the PEP-GAG gel to progress successfully through clinical trials, where it will be essential to be able to identify exactly which patients will benefit and carefully regulate the procedure to avoid the risk of complication.

These challenges require a multidisciplinary approach encompassing aspects of mechanical engineering and simulation alongside chemistry, biology, imaging and image processing

The aim of this project is to optimise aspects of the PEP-GAG hydrogel nucleus augmentation procedure so that it can be more effectively translated to clinical practice.

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.