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Low back pain is the leading cause of disability in the developed world and has an enormous social impact on patients and their families, as well as a devastating economic impact on healthcare budgets. Back pain is strongly linked to lumbar intervertebral disc degeneration, with severe degeneration being associated with a two-fold increase in chronic lower back pain. In addition to back pain, disc degeneration can lead to disc prolapse and radiculopathy, and is thought to be the precipitating cause of most degenerative conditions affecting the lumbar spine. The causes of disc degeneration are complex and multifactorial; including genetic, nutritional and mechanical factors. An overall decrease in resident disc cell number and function, and cellular responses to nutritional deficiencies, leads to alterations in both the cartilaginous and proteoglycan matrix components of the disc. An imbalance between extracellular matrix degradation and synthesis results in progressive dehydration, collapse and failure of the disc. Disc degeneration, like many degenerative diseases, is progressive as the disc has little intrinsic healing ability. The management of low back pain and radiculopathy can be a source of frustration for patients and clinicians due to a lack of treatment options available to successfully manage all patients. Initial treatments include conservative therapies such as analgesics, physical therapies and multimodal pain management strategies. When these non-operative treatments fail, surgical interventions such as lumbar fusion, microdiscectomy or total disc arthroplasty are commonly performed. Despite these surgical interventions, many patients continue to have chronic pain and disability. Substantial progress has occurred in the fields of regenerative medicine, tissue engineering and stem cell therapies in recent years. Clinical trials have commenced utilising cell-based biological therapies to treat many common diseases, including those affecting the musculoskeletal system. Degenerative discopathies are no exception, with growing interest from clinicians and researchers to find biological or regenerative strategies to replace or augment current treatment paradigms. Culture expanded disc chondrocytes and mesenchymal stem cells are among the cells, currently under investigation by researchers, which have been shown to restore the cartilaginous matrix of the disc. These cell-based treatments are still, however, in their infancy. Given the enormous suffering of patients worldwide with disc disease, and the inadequacy of current treatments, the pursuit of new biological therapies to reverse the degenerative cascade is crucial. The studies presented in this thesis were aimed at investigating the potential of allogeneic mesenchymal precursor cells (MPCs) to promote lumbar intervertebral disc regeneration. MPCs are a pure monoclonal cell population, derived by immunoselection, which have been shown to have chondrogenic potential. The proprietary MPCs used in these studies were provided by Mesoblast Ltd. These MPCs have already been shown to be efficacious in preclinical animal models of disc degeneration, and translation to clinical trials is currently underway. The optimal dose, cell carrier and best method of administration has, however, not yet been determined. The preclinical studies presented in this thesis utilise an ovine model of lumbar disc degeneration. The lumbar sheep spine is anatomically, mechanically, biochemically, and radiologically similar to the human spine, making it an accepted model for spinal studies. An ovine annular injury model was optimised and validated prior to its use as the starting point to test potential regenerative MPC therapies. Following demonstrated successful induction of disc degeneration, the ability of different doses of intra-discally injected MPCs, together with a range of different cell carriers, to repair the damaged disc was assessed. Standard outcome measures, including radiology, histology, biochemistry and disc morphology, were used to assess disc regeneration. In addition to injecting cells into the degenerate disc, a novel method of administering cells at the time of microdiscectomy was developed using a fibrin glue matrix to retain transplanted cells within the disc defect following microdiscectomy. The goal was to allow surgeons to administer regenerative therapies at the time of surgery when, usually, no attempt to repair the disc is made. The results of these studies demonstrated that surgically induced annular injury reliably and consistently produces degeneration in the ovine lumbar spine and that this model can be used as the starting point to test potential regenerative therapies. It was demonstrated that a low dose of MPCs (0.1 million versus 0.5 million cells), injected intra-discally, leads to significant restoration of disc structure and composition, and that regeneration was enhanced by the co-administration of pentosan polysulfate with the MPCs. Pentosan polysulfate is a semi-synthetic polysaccharide, which has been used to treat osteoarthritis in human and veterinary practice and has been shown in vitro to promote MPC proliferation and chondrogenesis. It was also shown that MPCs can be administered within a fibrin matrix, at the time of microdiscectomy, to improve disc degeneration status. Results from the studies presented have laid the foundation for further novel preclinical studies aimed at determining the mechanisms by which transplanted cells impart their clinical benefit in disc regeneration studies. The preclinical data obtained in these studies has been used to design and develop a large, phase-3 human clinical trial utilising MPCs to treat back pain. Awards: Winner of the School of Clinical Sciences Head of School’s PhD Excellence in 2014. |
