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Optimisation of a chronically implanted catheter for intraparenchymal delivery of therapeutics to the brain

Lewis, Trefor 2019. Optimisation of a chronically implanted catheter for intraparenchymal delivery of therapeutics to the brain. PhD Thesis, Cardiff University.
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Delivering drugs to the brain to treat degenerative diseases and other conditions is challenging because of the blood brain barrier, which acts as a filtration system preventing over 99 % of large, therapeutic molecules from entering the brain from the blood. A first-in-man study, delivering drugs directly through chronically implanted catheters inserted deep into the brain, formed the basis of this project. The short and long-term distribution data from this clinical study provided the direction of this research. Surgical planning guidelines were created which provide device specific, numerical values to optimise retention of infusate within target neuroanatomy. Optimisation of these implanted catheters was assessed through device characterisation, material investigation, development of miniaturised delivery systems for in vivo investigations and the creation of a finite element model of infusions into porous ‘brain’ matter. Despite dissimilar mechanical properties to brain tissue, agarose gel has superior permeability and optical properties over composite hydrogels for the characterisation of a recessed step catheter. In vitro experiments varying catheter features and infusion regimes identified significant changes in the distribution patterns of infused fluids which propagate through porous substrates, such as gels or the brain. By adjusting the catheter step length and peak volumetric flow rate, optimisation of implanted catheters could maximise coverage of target neuro anatomy. Gliosis around the implanted catheter was anticipated as a result of the immune response to injury. Through experimentation gliosis was shown not to be exacerbated by intermittent infusions. The extent of injury during implantation plays a greater role. Changes in clinical infusion distribution patterns may have been linked to observations of lower gliosis levels around the same time as test infusions occur clinically (1month post implant). Longer recovery periods could provide improved reliability of test infusions to inform users ahead of setting prescriptions for extended infusion regimes.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Engineering
Uncontrolled Keywords: Recessed Step Catheter; Convection-Enhanced delivery; CCb; Neurodegeneration; Intraparenchymal; Parkinson's Disease.
Date of First Compliant Deposit: 22 October 2020
Last Modified: 22 Oct 2021 01:30

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