Evans, Rachael Elizabeth; (2020) Biomaterial encapsulation to improve cell therapy for Parkinson's disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Current therapeutic approaches for Parkinson’s disease (PD), such as administration of levodopa and dopamine agonists are not ideal as they are only effective in the early stages of the disease. With PD being the second most common neurodegenerative disorder new therapeutic approaches are of great necessity. Over the past decade, cell therapy for CNS injury and disease has looked extremely promising. However, both pre-clinical and clinical evidence shows high rates of cell death after implantation and one cause of this is the host cellular response. The overall aim of this programme of work is to develop an advanced therapeutic for PD which overcomes the challenges of cell survival, focusing on protecting the cells from detrimental host glial cell and immune responses by synaptically isolating therapeutic cells in a hydrogel. Human induced pluripotent stem cells (hiPSCs) were successfully expanded and differentiated to dopaminergic neurons (DA-hiPSCs). A new protocol for encapsulating cells in an alginate hydrogel was developed and optimised using SHSY5Y cells. Alginate gels were then used to encapsulate DA-hiPSCs and the ability of encapsulation to protect cells was tested in vitro. Formulations of alginate hydrogels in microbeads and made using ThinCert™ 24-well plates were characterised for their physical and mechanical properties for use as a transplantable biomaterial for the CNS. Alginate hydrogels were further optimised to reduce the host response with the addition of poly-l-ornithine and hyaluronic acid. Local delivery of the immunosuppressant tacrolimus (FK506) was explored through the construction of drug-eluting nanoparticles using PLGA and PCL electrospraying. Results indicated that encapsulation of DA-hiPSCs using alginate has the potential to protect therapeutic cells from detrimental host cell responses and that synaptic isolation from host neurons is a new paradigm for PD cell therapy to be explored further. Along with the combination of immunosuppressant FK506 for local delivery, the approach shows promise for improving cell survival in transplantation for PD.

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