PhD Studentship: 3DBioFractal: A Model Multi-organ Culture Platform for Tissue Engineering and Engineering Biology

The limitations of animal models in bioscience research and whether they inform accurately on human physiology, pathology and therapies is well understood. They provide useful biological complexity, but many physiological mechanisms remain hard to interrogate. As a result, interest in entirely synthetic trustworthy “surrogate human” platforms modelling healthy physiological interactions between tissues and organs is growing.  These systems can also meet objectives of Replacement, Reduction and Refinement in the use of animals in research.  A series of micro-scale “body-on-a-chip” platforms that use cell and tissue cultures grown in controllable micro-fluidic environments with “organs” comprising a few thousand cells have been developed for screening and toxicity studies.  Each different type has contending strengths and limitations.  In this field there is particular interest in eventually creating model systems that use the expanding roster of iPSC-derived human mini-organs e.g. mini-livers, -guts, -brains etc (organoid technologies) as the living components. 

In this project we will develop a flexible “meso-scale” model, multi-organ system (rather than a micro system) and avoid the engineering challenges of miniaturisation to microfluidic scale.  This will create a platform accessible to “hands-on” experimental scientists rather than “chip” devices made for large scale screening purposes. The ambition is for the device to allow mixtures of monolayer cell (co)cultures, 3D organoid cultures, tissue explants and also synthetic bio-printed tissue components to be composed in any combinations required by the investigator to create a stable system for experimentation. It will integrate microscopy, spectroscopy, electrochemical and other analytic approaches for analysis of tissue health and performance.  An existing baseline device supporting serial, parallel or mixed perfusion paths over the different components will be adapted to allow tissue chambers to be manipulated in conventional flow hoods and incubators, including those mounted on microscopes stages. 

Working at the meso scale will address 5 key challenges to experimental control through:

(i) separate maturation of the component organ cultures and tissue quality control (using functional markers) before their combination.  For this project this will specifically include:

(a) liver (iPSC-derived spheroids)

(b) kidney (endothelial cell cultures & explant tissue)

(c) heart (bio-printed high-density co-cultures).

(ii) accurately balanced ratios of organ size - a problem in micro fluidics when cell proliferation rates are often mismatched,

(iii) creation of realistic differences in perfusion rates and fluid residence times on tissues,

(iv) avoidance of miniaturisation problems e.g. fabrication quality control; bubbling; evaporation (nutrient, osmolarity, pH changes); shear stresses; channel occlusion,

(v) incorporation of realistic mini-organs/tissues of increasing size expected to be available as engineering biology research gradually produces larger “parts” for therapeutic grafts.

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