The role of progenitor stem cells in promoting cervical interbody fusio

Abstract

Anterior cervical discectomy and fusion accounts for up to forty percent of all spinal fusion procedures and is the most common surgical approach employed for treating cervical spondylosis or discopathies. These conditions may cause pain, weakness and sensory disturbance collectively termed radiculopathy due to nerve root compression. If the spinal cord is compressed, cervical myelopathy may result. Cervical myelopathy causes progressive neurological symptoms such as disturbance of gait or hand dexterity, which are the most devastating sequelae of degenerative disc disease. If conservative measures have failed, anterior cervical discectomy may be indicated as it decompresses the neural elements. Following the discectomy however, the void in the interbody space needs to be stabilised and there are several options for doing this. Iliac crest autograft bone has traditionally been the gold standard graft material for cervical fusion, however it is associated with the potential for donor site morbidity. Alternatives, such as synthetic bone graft substitutes and cadaver bone allograft, have limited osteo-inductive properties and, whilst they avoid donor site morbidity, they can result in inferior fusion rates compared with autograft. Use of allograft has also been associated with graft rejection, resorption, infection and collapse. Bone substitutes are osteoconductive per se; meaning they provide a matrix into which local cells including endogenous mesenchymal stem cells (MSCs), blood borne cells and osteoblasts can integrate and produce bone. Endogenous MSCs are reduced with age, a factor that can reduce bone fusion. Fusion rates may be decreased in about forty percent of patients undergoing multilevel surgery or with conditions such as rheumatoid arthritis, smoking or using anti-inflammatory medications. Non-union or pseudoarthrosis following anterior cervical discectomy can result in recurrent radiculopathy and neck pain which may require reoperation. Recombinant bone morphogenetic proteins (rhBMPs) have been used as osteo-inductive agents aimed at increasing cervical interbody fusion rates, but have been reported to result in life threatening complications, including airway and neurological compression. There is a need, therefore, for agents that can safely and effectively increase cervical fusion rates. The studies in this thesis aimed at investigating the potential of allogeneic mesenchymal precursor cells (MPCs) and amnion epithelial cells (AECs) in promoting cervical interbody fusion. Both of these progenitor cells have previously been shown to have osteogenic potential. The MPCs are a pure monocloncal cell population derived by immunoselection and were provided by Mesoblast. The AECs were derived by our group and offer the advantage of non invasive collection and no ethical issues. Preclinical studies were undertaken in the ovine cervical model, as this is a wellestablished model with anatomical, biomechanical and radiological similarities to the human cervical spine. These studies were designed to comply with regulatory requirements so that rapid translation to human clinical trials could follow. Fusion rate and quality as well as safety both systemically and at the fusion site were assessed using outcome measures which included plain and functional radiography, computerised tomography, chemical pathology, gross and microscopic pathology, histology, histomorphometry, fluorochrome analysis and biomechanical assessment. The preclinical studies revealed that the MPCs resulted in increased fusion rates compared to controls with bone substitute or autograft. Two doses of MPCs were tested and compared and no significant differences were found between doses. The study conducted using AECs did not result in significant fusion. A clinical study protocol was then designed and submitted for human ethics approval, which was granted. A clinical study has now commenced based on the results obtained in the preclinical studies, using MPCs.