A bioengineering platform for the multiparametric and quantitative control of the cell environment across scales

Cells can generate forces. By pulling on their surrounding, the cells can sense how stiff or soft their environment is. Cells are also receptive to chemical signals. Both chemical and mechanical signals influence cell function, whether it divides, if it should move in any given direction or if it should differentiate. Understanding this process is fundamental if we want to understand how the cells build tissues and organs.
How chemical and mechanical signals are integrated by the cells is unclear. One of the reasons for this is that decoupling the two experimentally is very challenging. In the body, these cues are largely intertwined and the cell environment is very complex.
In this proposal we are requesting funding for an equipment that will allow us to build cellular environments in which we will be able to control the stiffness of the material independently of the chemistry of the environment. This will enable us to determine with great precision how each specific parameter of the cell environment affect different function of the cells or how they collectively organise to build tissues. We will use this knowledge to generate new in vitro models of organ physiology and study how ageing affects their function.
The equipment will also be offered as a service to the wider community of researchers in Edinburgh. This technology is currently not available in our institutions but the demand is increasing rapidly and attracts interest from researchers across diverse fields of research.

Cells can sense a variety of extrinsic cues that encompass both the biochemical (diffusible signals, extracellular matrix) and physical (stiffness, geometry, topography) properties of their micro-environment. These cues strongly influence cellular processes. They contextualise the genetic and epigenetic state of the cells to dictate function, differentiation and ultimately how cells self-organise to form tissues and organs. Much remains to be understood about these processes notably because studying these events in vivo where signals are tightly entangled is extremely difficult. It is therefore a necessity to manufacture in vitro niches where both chemical and physical cues are precisely controlled and uncoupled. Niche manufacturing is also required to establish robust in vitro models of human and animal physiological functions or to produce synthetic systems with novel properties that can benefit society.
We are requesting funding for a revolutionary platform, PRIMO, that leverages recent technical breakthrough to enable the precise engineering of cellular environments. PRIMO meets all our requirements: 1) effectiveness: the mechanical, biochemical and geometrical properties of the environment can be fine-tuned and decoupled with micrometer scale resolution. 2) versatility: modalities can be combined, substrate design with PRIMO is virtually unlimited 3) efficiency: PRIMO permits reproducible and scalable assays enabling high content approaches 4) accessibility: PRIMO makes the fabrication of complex substrates accessible to novice bio-engineers.
Hosted in the Centre for Regenerative Medicine in Edinburgh, the equipment will provide unique research and training opportunities to study niche mediated cell behaviour and create engineered cell systems. In the longer term we will explore biomedical applications and develop interactions with other groups in both industry and academia, thereby enhancing UK capabilities and direct relevance to BBSRC priorities.

The main goal of the PRIMO platform procurement at the UoE is to satisfy a rapidly increasing demand for access to the manufacturing of controlled cellular environment. Indeed, sophisticated in vitro environments are often a requirement for research in fundamental cell biology, synthetic embryology and regenerative medicine and also to bring cell systems with potential biomedical applications towards commercialisation.

There are multiple stakeholders to the acquisition of the PRIMO platform:
* Biologists, chemists, bio-physicists and medical scientists based in the UoE and their collaborators in the UK and overseas
* Pharmaceutical and regenerative medicine industry
* Students
* General public

UoE Academic
UoE scientists would be among the first beneficiaries of the equipment - providing them with entirely new opportunities to address their specific questions. We have already identified several groups of interested parties among academics within the UoE, including members of the centre for synthetic biology (see letters from Professor Susan Rosser and Professor Jamie Davies), members of the Edinburgh organoid network (see letter from Dr John Mason) as well as UKRMP scientists (see letter of Professor Stuart Forbes). This convergence of interests towards the technology will foster new interactions on the Little France campus where the equipment will be hosted but also across the campus of the college of science and engineering and college of veterinary medicine.

Pharmaceutical and Regenerative medicine industry
Applicants and collaborators in this proposal have numerous links with a range of industrial partners such as (Bayer) as well as with Prof. Neil Carragher head of Edinburgh Drug Discovery who already provided a letter of support.
3D cell culture and organoid production have strong potential for the pharmaceutical industry because they better mimic the complexity of the in vivo environment. PRIMO is the ideal platform to build standardised substrates and address the current bottlenecks in the field of organoid production; that is reproducibility and scalability, and therefore to contribute in bringing in vitro models developed by us and other UoE researchers towards industrial applications.

Students
Both academic research and the industry rely on highly qualified, motivated and creative people to conduct their activities and innovate. Procurement of the PRIMO platform will foster truly interdisciplinary science as exemplified by the research in this proposal. This will contribute in training staff and student into the fast-advancing field of bioengineering adding to their biologist skillset. This will contribute in increasing student's employability as well as increasing the critical mass of qualified professionals to satisfy cutting edge research and biotech industry demand.

General public
PRIMO will transform our ability to build engineered cell system with new properties. It will also help replicating in vitro early human developmental stages. It will be important to engage with Philosophers and the general public in order to ensure that a real dialogue is established and that responsible research is conducted with PRIMO and stem cells.

Overall, we are convinced that procurement of the PRIMO plateform will place us well to strengthen competitiveness and attractiveness of the UoE and the UK within the fast paced fields of stem cell science, regenerative medicine and synthetic biology from the academic, societal and economic perspective