Lab-based produced vascularised tissue for in vitro lab on a chip models of healthy and diseased tissue

Lead Research Organisation: University of Sheffield
Department Name: Materials Science and Engineering

Abstract

An important research strand in biomaterials is the development of in-lab grown organs, which are increasingly mimicking the structural and biological complexity of human organs. These organs-on-a-chip are increasingly developed as an alternative to the use of animals in pharmaceutical testing. However the lack of perfusion through vascularisation remains an obstacle in the development of physiological tissue-on-a-chip models. Current models using microfluidic perfusion lack sufficient scale and complexity. Ex-vivo tissue slice cultures are also only suitable for very short-term culture. The project will utilise in house developed technology to build an in vitro model of vascularised tissue. This technology incorporates a prototype vascular network in a porous material and allows for vascular outgrowth to occur in a hydrogel-based well where we can place cells, cell spheroids or even small biopsies. We will use perfusion bioreactors to study the vascular outgrowth within the scaffolds to obtain a lab-on-a-chip device that can be used for long term observation of vascularisation in healthy and diseased tissue models. This will be developed to present an in vitro alternative to in vivo testing platforms, such as the mouse dorsal skin fold model. This in vitro model will be used to explore the vascularisation of healthy and diseased tissue models. We aim to explore healthy and cancer tissue models. If successful, this device will fill an important unmet need as an in vitro testing platform.

This project aims to build an in vitro model of vascularised subcutaneous connective tissue, which can be grown in a lab environment and can be assessed as a lab-on-a-chip. We have recently developed the technology to enable this project, in particular we have developed scaffolds with prototype vascular networks based on electrospun membranes. We have also recently developed additive manufacturing routes to build vascular networks within polymerised High Internal Phase Emulsions (polyHIPEs). These materials will form the basic technology to develop the vascularised tissue model, this model will be used to answer the following questions:
1) Can a vascularised tissue model be constructed for medium term cell culture (up to a month) that recapitulates the basic physiology of native tissue. We will assess the following (i) cell growth and survival, (ii) vascular sprouting and network formation (iii) vascular permeability and flow and (iv) extracellular matrix formation.
2) This model will be used to investigate the vascularisation of tumour spheroids and potentially small tumour biopsies. We will focus on studying the angiogenesis promoted by the tumour.
3) The model will be used to assess vascular targeting therapies to understand if the model can predict any scenarios relevant to the pharmaceutical industry.

This project combines additive manufacturing and novel polyHIPE biomaterials to produce a preclinical testing platform. This project aims to overcome the geometric limitations of soft, biopolymer-based, hydrogels by developing a hybrid biomaterial composite, combining hydrogels and porous synthetic polymer scaffolds, to enable a diverse range of new 3D cell culture applications. The focus is to build a small soft tissue mimic, with inclusion of prototype vasculature, to be used as a lab-on-a-chip testing platform.

The aim of this PhD project is to combine biodegradable polyHIPE scaffolds with hydrogels. The hydrogel mimics the extracellular matrix and is structurally reinforced with a polymer scaffold, providing the mechanical support of natural tissue. This PhD will develop these scaffold-reinforced hydrogel composites and examine their physical properties while also exploring their use as 3D culture scaffold. We will investigate a number of natural hydrogels (e.g. collagen and matrigel). In addition, we will explore the use of self-assembling peptides (such as Peptigels as developed by Manchester Biogel).

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S022201/1 01/04/2019 30/09/2027
2343382 Studentship EP/S022201/1 01/10/2019 30/09/2023 Caitlin Jackson