Jones, Julia Miriam; (2018) Development of 3-Dimensional Muscle Organoid Collagen Model as a Standardized Assay for Testing Novel Biomaterials. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Traditionally in vitro 2D cultures were used for pre-clinical tests, followed by complex in vivo assays. However, progression has seen the paradigm shift to in vitro 3D tissue engineered (TE) cultures. Nestled within the multi-disciplinary field of TE is the niche of skeletal muscle (SkM). The TE SkM nexus to preclinical testing in this thesis drives to be an intermediary platform prior to in vivo testing for drug and biomaterial development. The aim of this project was to develop new configurations of SkM constructs (RMO and PEEK) for biomaterials testing. However, the relevance of SkM TE is only useful if the cell environment within the construct matches the native tissue in terms of myoblast density, myotubes formation and appearance. Assessment of the success of myotube formation or its degradation was by comparisons of constructs to a list of parameters (myotube index: width, length, number of myotubes, etc and was inclusive of mRNA and construct deformation). The experimental investigations looked to understanding the influence of chamber type (configuration), on formation or morphological appearances when compared to the established 8WC SkM model. The RMO chamber failed to facilitate 3D culture. However, PEEK chambers’ constructs showed similar comparisons to the 8WC, but differences with changes to conditions. As well as novel biomaterial testing via simvastatin hyaluronic acid-dopamine nanoparticles (Sim NPs) delivery, with PEEK constructs, showed reduced degradation of myotubes in comparison to Simvastatin in liquid form. Finally, material degradation was explored by use of fluorescent PLGA microspheres. Subsequent PLGA investigation saw no degradation, but reported obstruction of myoblasts, which prevented myotube formation. This work has demonstrated ways to assess myotube outcomes, also explored methods for SkM construct optimisation; as well as methods and subsequent SkM models for biomaterial testing. This demonstrated the versatility of the SkM construct and the variety of parameters that can be used to track biomaterials in the construct or their interaction with cells over time, enabling real-time monitoring at the implant site.

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