Wong, PFJ; (2016) Development of Next Generation 3-Dimensional In vitro Soft Tissues Models for Biomaterial Testing: Controlling Construct Properties with Fluid Flow. Doctoral thesis , UCL (University College London).

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Abstract

Pre-clinical biomaterial development and testing have traditionally relied on 2D in vitro, or complex in vivo assays. It is essential for the cell environment to match the natural tissue in terms of matrix density, architecture, components (including stress/strains) for tissue models to behave in a natural manner. The aim of this project is to improve existing in vitro models for the biomaterial testing. Plastically compressed collagen hydrogels were used to create a simple and accessible 3D model. Improvement in hydrogel stiffness was achieved using pre-crosslinked, polymeric collagen, as a starting material. Hydrogels were formed by blending polymeric and monomeric collagens, which delayed the aggregation of collagen fibrils, and enabled cell incorporation at physiological pH. Plastic compression of the novel hydrogel resulted in stiffer constructs; however, during compression, cells were exposed to reversible (i.e. using mobile macromolecules) increases in cell-damaging fluid shear stresses. In the material degradation model, it was found that the release rates of PLGA degradation products were influenced by cells in the collagen matrix; and differed significantly between 2D (24 hours) and 3D (7 days) models. Imaging of cells cultured within the biomaterial also demonstrate the up-take of biomaterials within cells within the model after 10 days in culture. Nanoparticle drug delivery via hyaluronan nanoparticle (HA-NP) was improved by increasing blockage at the fluid leaving surface (FLS). The HA-NP was designed to gradually release trapped simvastatin, which was measured indirectly via BMP2 production over time. Although results were inconclusive, initial experiments demonstrated sustained BMP2 production by cells over 5-9 days. This work has demonstrated novel ways to improve the stiffness of the model construct, and an improved understanding of particle movement within the hydrogel during plastic compression. The models for biomaterial testing have demonstrated that it was possible to track biomaterials in the construct/ cells over time, enabling real-time monitoring of the biomaterial and cells at the implant site.

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