Screening Nanoparticle Dynamics on Modular Tumours-on-a-chip devices

Abstract

Understanding distribution of nanoparticles across a tumour is important for theranostic applications. However, many biological barriers need to be overcome to accumulate nanoparticles across a tumour, and where testing can be expensive and time consuming. The work presented is aimed towards developing a fast prototyped testbed for the screening of nanoparticle distributions. The tumour-on-a-chip device was designed to be low cost and accessible to researchers using 3D printed microfluidic moulds compared to tradiational microfluidic fabrication. The validation of diffusion was performed using simulations and experiments demonstrating particles experiencing Brownian motion. Furthermore, a hydrogel environment was loaded over 16 hours replicating a tumour-like environment based on dynamic viscosity. An image processing algorithm was developed for continuous analysis providing novices with a one-click analysis. The image processing algorithm aided in alignment, reducing illumination fluctuations as well as quantifying nanoparticle penetration distances. Three thresholds were investigated counteracting illumination fluctuation measuring similar penetration depths within a hydrogel environment. Further comparison of penetration depths was made between 20nm, 40nm, 40nm streptavidin and 100nm FluoSpheres® within a 4% gelatin methacrylate hydrogel. Sub- and super-diffusion correlated with hydrogel heterogeneity and nanoparticle penetration depths. Significance of 12µm between 20nm FluoSpheres® nanoparticles, 13µm ± 6, and 100nm FluoSpheres® nanoparticles, 0µm depth (p < 0.05). Additionally, a protocol was presented to characterise hydrogel porosity and interconnectivity. The permeability of a hydrogel is important for the transport of nutrients and oxygen for cell growth and survival. The proposed method does not introduce artefacts unlike freeze drying techniques. Also, this method preserves a biological relevant hydrogel. The method was tested with poly(ethene glycol) diacrylate (PEGDA) and bio-ink (alginate pluronic solution) hydrogels. The method is low cost and directly measures the permeability of a hydrogel. The use of the tumour-on-a-chip allows for bio-engineers to test a variety of nanoparticle designs. Further work is required to validate the correct the threshold to measure nanoparticle depths. Currently the tumour-on-a-chip screens nanoparticle distributions in time but requires 3D images to validate the diffusion space. The continuous measure over time allows for measuring sub- and super-diffusive processes. Changing hydrogel porosity and interconnectivity will change nanoparticle diffusion. The novelty of the device aims to bridge the gap between in vitro and in vivo experiments improving nanoparticle therapies. The advances will aid in personalised medicine tailoring medicines to individual tumour environments.

Date of Award	1 Oct 2019
Original language	English
Awarding Institution	The University of Bristol
Supervisor	Adam W Perriman (Supervisor) & Sabine Hauert (Supervisor)