Development of a 3D human in vitro model of pancreatic beta cell health
Lead Research Organisation:
University of Nottingham
Department Name: Sch of Pharmacy
Abstract
Diabetes mellitus is a major health issue with ~390 million people affected worldwide (IDF Diabetes Atlas 6th edition,
2014). Most diabetics are type 2 (T2D), typically characterised by the loss of pancreatic beta cell function and beta cell
mass and peripheral insulin resistance. Whilst current therapies do provide some level of glycaemic control, they do not
prevent the debilitating long-term consequences of the disease. In the on-going search for better treatments, there is now a
real focus on strategies that aim to preserve the function of remaining beta cells or replenish beta cell mass.
To support this new focus of diabetes research, this project aims to develop a human 3D in vitro model of pancreatic beta
cell health / beta cell proliferation. No such commercial model currently exists. The model will be developed using native
human islets and Asterand Bioscience's (Asterand's) proprietary 3D cell culture platform. The consortium will then explore
whether a more sustainable cell source can be utilised (eg., iPSC-derived beta cells) and ultimately whether the
established model can be miniaturised using 3D printing. The 3D printing work is to achieve highly accurate spatial
dispensing of beta cells onto membranes in well plates that the currently commercial platform is based on. The effects of
dispensing conditions on cell viability and functions will be investigated to identify an optimal processing condition for
dispensing beta cells. In addition, how cell population influences cell function will be studied by dispensing cell samples
with different sizes. The proposed cell printing solution combined with technologies developed by two industrial partners will
create a unique manufacturing advantage allowing the production of off-the-shelf products for drug discovery.
2014). Most diabetics are type 2 (T2D), typically characterised by the loss of pancreatic beta cell function and beta cell
mass and peripheral insulin resistance. Whilst current therapies do provide some level of glycaemic control, they do not
prevent the debilitating long-term consequences of the disease. In the on-going search for better treatments, there is now a
real focus on strategies that aim to preserve the function of remaining beta cells or replenish beta cell mass.
To support this new focus of diabetes research, this project aims to develop a human 3D in vitro model of pancreatic beta
cell health / beta cell proliferation. No such commercial model currently exists. The model will be developed using native
human islets and Asterand Bioscience's (Asterand's) proprietary 3D cell culture platform. The consortium will then explore
whether a more sustainable cell source can be utilised (eg., iPSC-derived beta cells) and ultimately whether the
established model can be miniaturised using 3D printing. The 3D printing work is to achieve highly accurate spatial
dispensing of beta cells onto membranes in well plates that the currently commercial platform is based on. The effects of
dispensing conditions on cell viability and functions will be investigated to identify an optimal processing condition for
dispensing beta cells. In addition, how cell population influences cell function will be studied by dispensing cell samples
with different sizes. The proposed cell printing solution combined with technologies developed by two industrial partners will
create a unique manufacturing advantage allowing the production of off-the-shelf products for drug discovery.
Planned Impact
The main motivation of this project is to develop a better human 3D in vitro model of pancreatic beta cell health/proliferation
for applications in drug discovery. In the on-going search for better treatments, there is now a real focus on strategies that
aim to preserve the function of remaining beta cells or replenish beta cell mass. No commercial model currently exists for
this purpose. In vitro tissue models with more predictive power can potentially reduce the cost of drug development as well
as increase the safety of new drugs. Moreover, beta cells derived from iPS cells can potentially become a more sustainable
cell source compared to primary cells and have less risk of immunogenicity associated with cell implantation.
The capacity in dispensing primary and iPSC-derived beta cells with spatial accuracy will not only facilitate the fabrication
of miniaturised in vitro cell culture models but also open up the opportunity of fabricating implantable beta cells constructs
to treat diabetes. The expected outcomes of the project are a new sustainable beta cell source, a miniaturised in vitro
model platform and manufacturing know-how in dispensing beta cells. Therefore it has a significant impact in drug
development and regenerative medicine in the long term. This project has the potential to contribute to the economic
competitiveness of UK by increasing the product portfolio of existing UK SMEs as well as opens up new business
opportunities in the regenerative medicine area. This project will also output a trained researcher with a set of multidisciplinary skills from the academic partner. New employees will be hired by the industrial partners for this proposed
research activity. Assuming successful development, additional scientists would be employed by the industrial partners to
take the research service to market and deliver the resulting commercial projects.
for applications in drug discovery. In the on-going search for better treatments, there is now a real focus on strategies that
aim to preserve the function of remaining beta cells or replenish beta cell mass. No commercial model currently exists for
this purpose. In vitro tissue models with more predictive power can potentially reduce the cost of drug development as well
as increase the safety of new drugs. Moreover, beta cells derived from iPS cells can potentially become a more sustainable
cell source compared to primary cells and have less risk of immunogenicity associated with cell implantation.
The capacity in dispensing primary and iPSC-derived beta cells with spatial accuracy will not only facilitate the fabrication
of miniaturised in vitro cell culture models but also open up the opportunity of fabricating implantable beta cells constructs
to treat diabetes. The expected outcomes of the project are a new sustainable beta cell source, a miniaturised in vitro
model platform and manufacturing know-how in dispensing beta cells. Therefore it has a significant impact in drug
development and regenerative medicine in the long term. This project has the potential to contribute to the economic
competitiveness of UK by increasing the product portfolio of existing UK SMEs as well as opens up new business
opportunities in the regenerative medicine area. This project will also output a trained researcher with a set of multidisciplinary skills from the academic partner. New employees will be hired by the industrial partners for this proposed
research activity. Assuming successful development, additional scientists would be employed by the industrial partners to
take the research service to market and deliver the resulting commercial projects.
People |
ORCID iD |
| Jing Yang (Principal Investigator) |
| Description | Data generated at University of Nottingham was shared with two industrial partners (BioIVT, DefiniGen). The industrial partners can utilise the liquid cell suspension dispensing process that was developed at UoN if they wish to incorporate it into their in vitro cellular systems for disease modelling and/or drug screening. The data generated at UoN included optimised parameters for cell suspension dispensing, viability of cells after dispensing, morphology and function of dispensed cells. |
| First Year Of Impact | 2018 |
| Sector | Pharmaceuticals and Medical Biotechnology |
| Impact Types | Economic |
| Title | Micro-valve dispensing |
| Description | We use a micro-valve dispenser to dispense a very small droplet (5 nL) containing cells(primary islet cells and induced pluripotent cell derived beta cells) into 96-well plates. The viability of functionality (mainly glucose stimulated insulin secretion) of these cells are characterised. |
| Type Of Material | Technology assay or reagent |
| Provided To Others? | No |
| Impact | This is still a ongoing project. We aim to miniaturised the existing cell-based in vitro models the collaborator (Asterand) is using. So with a limited amount of expensive human primary islet cells, more samples can be made to increase throughput. |
| Description | collaboration with Asterand and Definigen |
| Organisation | Asterand |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | I miniaturise the in vitro cell-based sample format that Asterand is using in drug screening. Currently human primary islet cells are manually dispensed into 24-well plates. With a micro-valve liquid dispenser, my team is able to dispense less cells into each well of a 96-well plate. Therefore, the cell-based sample format is miniaturised and has a higher throughput for drug screening. |
| Collaborator Contribution | Asterand supplies human islets, and associated techniques to dissociate, culture and characterise these cells. DefiniGEN supplies induced pluriipotent stem cells derived beta cells, and associated culture medium and characterisation methods. |
| Impact | This is a ongoing multi-disciplinary project. We have demonstrated that 3t3 fibroblasts can be dispensed with high viability into 96-well plates. We are now investigating human primary islet cells and stem cell derived beta cells. |
| Start Year | 2016 |
| Description | collaboration with Asterand and Definigen |
| Organisation | DefiniGEN |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | I miniaturise the in vitro cell-based sample format that Asterand is using in drug screening. Currently human primary islet cells are manually dispensed into 24-well plates. With a micro-valve liquid dispenser, my team is able to dispense less cells into each well of a 96-well plate. Therefore, the cell-based sample format is miniaturised and has a higher throughput for drug screening. |
| Collaborator Contribution | Asterand supplies human islets, and associated techniques to dissociate, culture and characterise these cells. DefiniGEN supplies induced pluriipotent stem cells derived beta cells, and associated culture medium and characterisation methods. |
| Impact | This is a ongoing multi-disciplinary project. We have demonstrated that 3t3 fibroblasts can be dispensed with high viability into 96-well plates. We are now investigating human primary islet cells and stem cell derived beta cells. |
| Start Year | 2016 |