Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.774680
Title: Inflammasome mediated response to biomaterials implanted in the peripheral nervous system
Author: Barone, Damiano Giuseppe
ISNI:       0000 0004 7961 8830
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Abstract:
Neurological disabilities carry an enormous burden on patients and communities, with almost no treatment strategies available in clinical practice. Implantable neural interfaces represent a promising tool, able to potentially restore loss of neurological function in brain, spinal cord or peripheral nerve injury patients. However, neural interfaces require selectivity and long-term stability, which are compromised by the physiological host-implant response (foreign body reaction - FBR), which surrounds the implant with fibrotic connective tissue. Little is known about the cellular and molecular mechanisms of FBR in peripheral nerves and all the treatments to date have shown to be not specific and unsuitable to be translated in clinical practice. The aim of this project is to elucidate the molecular mechanism involved in the early stages of FBR and peripheral nerve injury and identify a potential target able to reduce FBR, without affecting neuronal regeneration. Using RNA sequencing, I have determined the differential expression of genes (between day 1 and day 28 post intervention) between a normal mouse sciatic nerve (control), a crushed one (peripheral nerve injury PNI model) and one with a device implanted (FBR model). From this dataset, I have characterised the differences in the immune response between PNI and FBR and demonstrated the potential role of IL1b and the inflammasome in the treatment of FBR. Using in vivo knock-out models of the inflammasome, I have shown: reduction in the expression of molecules involved in inflammation and fibrosis (using RT-qPCR); reduction in scar thickness and increase in axonal regeneration (using histology). I have developed a protocol to manufacture implants (conduits - model of regenerative neural interface) impregnated with either dexamethasone (used as positive control) and NLRP3 inflammasome inhibitor (proposed intervention). I have demonstrated that localised delivery of a NLRP3 inhibitor reduces FBR scar thickness (at 3 months), without reduction in axonal count. This also corresponded with a possible reduction in IL1b production in the NLRP3 inhibitor group. Using RNA sequencing, I further characterised the differential expression of genes of the proposed treatment strategies (at 28 days post intervention) to investigate the molecular pathways and cell types involved in the interventions. These findings show that inhibition of NLRP3 inflammasome reduces inflammation and FBR in peripheral nerve implants, without compromising neuronal regeneration.
Supervisor: Fawcett, James W. ; Bryant, Clare E. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.774680  DOI:
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