Applied biomimetic microfluidics for embolisation applications: towards the reduction of animal models for therapeutic evaluation of embolic agents

Abstract

In vitro testing is a powerful tool for evaluating the performance of medical devices. This thesis presents the application of biomimetic microfluidic devices for in vitro characterisation of embolic microspheres, with respect to clinically inspired case-studies of the treatment of hyper-vascularised tumours.

A comprehensive literature review of in vitro characterisation methods identified areas of potential research associated with the flow distribution, physical attributes and drug delivery capabilities of embolic agents. Flow devices were designed to replicate sections of hepatic architecture; initially focusing on embolic penetration efficacy, and then expanding to involve circular channels of various sizes representative of human blood vessels.

Microfluidic testing was integrated into the development of novel radiopaque microspheres, providing novel assessment criteria for the selection of physicochemical attributes and aiding effective translation from in vitro to first-in-human studies. An in vitro vascular network device was then refined through collaboration with treating physicians and utilised for novel emulsion characterisation, as part of a pre-clinical screening study. Pharmacokinetic trends and handling investigated in this study enabled confirmation of performance behaviour predicted in vitro. To account for microvascular flow effects, a device representative of 3rd order hepatic bifurcations was utilised to investigate distribution of drug loaded embolics under clinically relevant flow conditions. Computational Fluid Dynamic modelling was applied for in silico prediction according to empirical observations indicating preliminary prediction capabilities.

In vitro drug elution in respect to core bead chemistry, size and dose density at the point of catheter delivery was investigated. Reported elution trends indicated the highest statistical level of in vitro – in vivo correlation with pre-clinical studies, providing better understanding of systemic plasma profiles generated in vivo. A separate gel model representative of porcine parenchymal tissue was employed to investigate the effects of external focused ultrasound on contact based drug diffusion. Diffusion rate was shown to be higher for non-radiopaque, smaller beads, aligned with findings from previous freeflowing elution models.

Finally, a case-study investigated the in vitro flow distribution of radioembolic microspheres with respect to particle density and the application of contrast agent concurrent to microsphere administration. The investigation was able to show that material density was not the overriding factor influencing distribution and a novel administration protocol combining contrast agent with saline injections for potential intra-procedural visualisation was proposed.

Overall, this thesis utilises novel compartmentalised in vitro devices to characterise embolic agent attributes, enable development of predictive models and provide potential methods for the reduction of animal testing. Devices and methods were incorporated into clinically inspired casestudies to demonstrate relevance and application to the field of interventional oncology.

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Identifiers

ORCID for Xunli Zhang: orcid.org/0000-0002-4375-1571

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