Injectable hydrogel for the regeneration of the intervertebral disc: evaluation using an ex vivo loaded disc culture model.

Low back pain affects 80% of the population at some point in their lives, costing millions to the UK economy. Approximately 40% of all low back pain cases are caused by disease in the joints in the spine, known as the intervertebral discs. These discs enable the spine to move, bend and flex and act to absorb load during normal daily activities.

Intervertebral discs are similar in structure to a jam doughnut, containing a soft gel (like the jam) surrounded by a stiffer elastic ring (like the dough in the doughnut). Disease of these spinal discs which is known as disc degeneration, is the result of abnormal cell behaviour and mechanical damage, which results in an increased production of natural chemicals which can damage the disc and stimulate local nerves, making the back very painful.

Current treatments for low back pain do not target the cause of disc degeneration so they do not cure the patient, they simply treat the symptoms to make it less painful. Right now, the only successful approach surgeons use is the removal of disc material (the jam) which has squeezed out of the disc which presses nearby nerves. This surgery prevents further compression of the nerve root, making it less painful, however this is only a suitable treatment for a small proportion of sufferers where the middle of the disc has squeezed out and compresses the nerves. Most patients with low back pain without nerve compression currently have very limited treatment options. We have developed a new material (NPgel) which is a liquid outside of the body and can be injected directly into the disc via a needle without the need for major surgery. Following the injection into the disc the material becomes a gel, with similar mechanical properties to intervertebral disc tissue. In addition the material can be mixed with stem cells taken from the patient's own bone marrow, which will allow the growth of healthy new disc material in the diseased discs. The material can also be mixed with chemicals that prevent the native diseased cells of the disc from causing any further damage.

Our material has the potential to stop the disease getting worse, whilst helping the growth of new disc tissue using the stem cells we inject into the disc. We have previously tested our gel material and shown it has similar mechanical properties to intervertebral disc tissue, and does not kill human bone marrow stem cells when they are mixed together. In addition we have previously shown that cells taken from healthy people and mixed into the NPgel change their behaviour and start producing the materials from which the spinal disc is made.

Before we are allowed to perform clinical trials in humans, a series of laboratory and animal experiments are essential. We have completed initial animal safety studies showing our gel is not toxic. Here, we aim to complete mechanical tests and determine the behaviour of the gel and injected cells in a laboratory set-up which mimics the environment of the human disc. Once successful, we aim to begin studies on large animals, which is necessary before we can conduct clinical trials of our gel on people. If all this goes well, it could be used as a treatment to cure disc disease in less than 10 years.

The treatment of degenerative disc disease (DDD) has advanced little in the last 20 years with current treatments addressing symptoms, rather than the underlying pathology. Thus there remains a large unmet clinical need and market opportunity for effective therapies to treat DDD. The NPgel developed by our group displays temperature dependant gelation and is fully compatible with a range of cells. The properties of NPgel give it the potential for launch as a standalone therapy, in the first instance, to provide improved therapeutic options for patients through regulation as a class III device. This can be combined, if necessary, with minimally manipulated BMPCs. We have completed initial in vitro cell behaviour studies demonstrating BMPC differentiation towards NP like cells, where they produce an appropriate matrix. We have also demonstrated in vivo safety of NPgel. However, prior to full efficacy testing within a large animal model it is essential to firstly determine the behaviour of NPgel and incorporated BMPCs under mechanical loads which mimic those seen in the human IVD. The complex loading pattern seen in humans is difficult to represent within animal models. In addition it is unethical to progress to large animal efficacy studies without firstly understanding this key behaviour. Therefore, we replace animal models with post mortem human tissue for this stage of the work, in accordance with the principles of the 3Rs which are strongly supported by the MRC. This project aims to investigate the mechanical properties of the NPgel under loads which mimic those seen in the human IVD. In addition we aim to address the behaviour of minimally manipulated BMPCs incorporated within NPgel and NPgel alone following injection into IVD tissue and cultured under loads which mimic those seen in the human IVD. Understanding this behaviour will then enable progression to pre-clinical efficacy testing in a large animal model, which we anticipate will lead to clinical trials.

Degenerative disc disease is one of the main causes of low back pain, which is the leading cause of disability, activity limitation and work absence throughout much of the world, imposing a high economic burden on individuals, families, communities, industry and governments. Low back pain is responsible for about one third of all work-related disability. For example, the WHO states that 149 million work days are lost each year in the USA due to lower back pain. Furthermore neck pain is also associated with disc degeneration and further impacts on disability, morbidity and economic burden. Our approach provides a number of key innovations and presents a potential paradigm shift in low back pain treatment and potentially neck pain therapy. Our strategy is the minimally invasive application of a hydrogel that can support the proliferation and differentiation of bone marrow progenitor cells thereby stimulating IVD regeneration. Upon successful completion of this project, NPgel would progress to clinical trials and a viable therapy would have a major impact on the current treatment strategies for LBP patients.

Successful development of this therapy will have a significant impact on the health and well-being of citizens in developed nations, contributing to wealth creation directly in the form of a new technology with significant commercial value and indirectly by reducing the number of work days lost through LBP. The change in emphasis, treating the cause of LBP rather than treating the symptoms, will lead to changes in organisational culture and practices in the health sector, reducing the hospitalisation time required for treatment. The IP generated during this project will be ripe for commercialisation; the European market for Minimally Invasive Spinal (MIS) devices is expected to exceed 90M Euros in 2017 (iDATA_EUSP09_RPT & iDATA_EUMIS11_RPT) and this technology could be a major contributor to this market in the future.

The economic as well as societal impacts of this work will lead to a worldwide advancement in the understanding of regenerative therapies for musculoskeletal tissues. NPgel has the potential to be a disruptive platform technology, impacting upon researchers studying regenerative strategies for a wide variety of musculosksletal tissues, indeed we have strong data supporting its use for bone regeneration.
The project is multidisciplinary in nature and this will facilitate the training of highly skilled researchers in a range of cross-disciplinary methods. Importantly the collaboration with the team in Amsterdam will provide a unique opportunity for the team from Sheffield Hallam University (SHU), to develop skills with organ culture loading systems, these skills will then be brought back to the UK where in the future such loading systems could be developed in the UK, which are not currently available which would benefit a number of UK groups. The project will impact on public acceptance and understanding of stem cells, polymer science, the ethical use of animals in research and regeneration therapies and the use of alternative model systems supporting the 3Rs principles.

Continued development and commercialisation of this material will lead to (i) a revolution in spinal regeneration therapy, (ii) the potential formation of a successful new company in the UK and (iii) a product with access to an untapped multi-billion dollar market worldwide.