Bioprocess development for production of 3D tissues to underpin creation of engineered meat

The way we feed ourselves is becoming a growing problem, growing population and income growth in many developing countries is fueling an increase in global meat demand. Animal agriculture has been responsible for around 14.5% of total man-made greenhouse gas emissions, takes up 70% of arable land and 27% of fresh water usage for maintaining livestock and feed production1. Traditional meat production and its role in perpetuating the climate crisis is a clear problem which is currently affecting the climate and is set to get worse.

Cultured meat represents a solution to this problem, by producing laboratory grown animal tissue from a small cell sample using laboratory techniques rather than livestock rearing and slaughtering. This technology has many benefits over livestock farming with drastic reductions in land and fresh water requirements as well as greenhouse gas emissions. Further, being manufactured under controlled conditions, the meat can be produced free from bacteria and viruses which could infect consumers. This is achieved without the excessive antibiotic usage that occurs in livestock farming which perpetuates the rise of antibiotic resistant diseases. Controlled manufacturing conditions also support customisable nutrient profiles which can be enriched in desired nutrients to eliminate deficiencies and have reduced levels of certain compounds such as cholesterol which are potentially harmful.

Cultured meat has come a long way since the first 250,000 Euro burger in 2013 with a recent Good Food Institute report depicting a growing industry with 366 million dollars of investment in 2020 alone. With the company Good Meat selling cultured chicken in a Singapore restaurant the race to bring commercially viable large scale cultured meat to consumers is under way. Despite the GFI reports encouraging statement that there are no more fundamental technological breakthroughs required for commercially viable large scale cultured meat, there is still much research needed to tackle the biochemical and engineering challenges of increasing affordability, scaling up production and mimicking the texture and nutritional profile of slaughtered meat.

This project aims to produce cultured meat tissues by engineering hydrogel capsules that will act as a 3D scaffold on which cells can grow into a 3D network. These encapsulated cells can be cultured within a bioreactor and the co-culture of different cell types can help replicate the complexity of meat tissue. In order to imitate livestock meat, cultivated meat will need a complex structure consisting of muscle, fat and connective cells which together provide the taste and nutritional value of meat. Bovine mesenchymal stem cells (bMSCs) will therefore be used in this project as not only are they easy and cheap to grow and easy to isolate but they also have the ability to differentiate into both muscle and fat cells, both of which are necessary for the co-culture of a complex meat-mimicking tissue2.

The hydrogel capsules on which these bMSCs will be grown will need to fit a range of parameters. They will need to be edible and provide a 3D structure suitable to allow adhered cell growth, these characteristics will be defined by the hydrogels biochemical make up and to thoroughly investigate ideal growth conditions a range of hydrogels and capsule sizes will be explored. Capsule size can be altered through fine tuning of production parameters, such as hydrogel injection rate and shearing force, and specific size ranges can be selected using membrane extrusion techniques.

This project aims to define an optimized process by which complex bovine tissue can be cultured using 3D hydrogel capsules, grown within a bioreactor for the scalable production of cultured meat.

1Stephens, N. et al. (2018) Trends in Food Science & Tech
2Hanga MP et al (2020) Biotech Bioeng; 117(10):3029-3039.

Humanised, 3D tissue models are finding interest due to current overly-simplified immortal cell lines and non-human in vivo models providing poor prediction of drug safety, dosing and efficacy; 43% of drug fails are not predicted by traditional screening and move into phase I clinical trials1. Phase I sees a 48% success rate, phase II a 29% success rate and phase III a 67% success rate [1]. The drug development pipeline is pressurised due to adoption of high throughput screening / combinatorial libraries. However, while R&D spend has increased to meet this growing screening programme, success, measured by launched drugs, remains static [2]. This poor predictive power of the >1 million animals used in the UK each year drives the 12-15 year, £1.85B pipeline, for each new drug launch [3]. Contract research organisations (CROs) are also similarly hit by these problems.

Drive to reduce animal experimentation in toxicology and outright banning of animal testing for e.g. cosmetics in the UK has driven companies to outsource or to adopt the limited number of regulator approved NAT models for e.g. skin [4,5].

Another key area that uses 3D tissues is the field of advanced therapeutic medicinal products (ATMPs), i.e. tissue engineering/regenerative medicine. Regulation is a major ATMP bottleneck. It is thus noteworthy that regulators, such as the UKs Medicines and Healthcare Products Regulatory Agency (MHRA), are receptive to the inclusion of NAT-based data in investigative medicinal product dossiers [6].

The lifETIME CDT will directly address these issues through nurturing of a cohort training not only in the research skills required to conceive and design new NATs, but also in skills based on:

- GMP and manufacture.
- Commercialisation and entrepreneurship.
- Regulation.
- Drug discovery and toxicology - a focus on the end product.
- Policy.
- Public engagement.

Our NAT graduate community will impact on:

- Pharma - access to skills that develop tools to unlock their drug discovery and testing portfolios. By helping train graduates who can create and deploy NATs, they will increase efficiency of drug development pipelines.

- ATMP manufacturers - the same skills and tools used to deliver NAT innovation will help to deliver tissue engineered / combination product ATMPs.

- CROs - access to skills to create platform tools providing more sophisticated approaches to the diverse research challenges they face.

- Catapult Centres - access to skills that provide innovation that can be deployed across the broader healthcare sector.

- Regulatory agencies e.g. MHRA - better education for the next generation of scientists on development of investigational new drug / medicinal product dossiers to speedup approvals.

- Clinicians and NHS - access to more medicines more quickly through provision of highly skilled scientists, manufacturers and regulators. NATs will help drive the stratified/personalised medicine revolution and understand safety and efficacy parameters in human-relevant tissues. Clinicians will also benefit from development of ATMP-based regenerative medicine.

- Patients - benefit from skills for faster and more economically streamlined development of new medicines that will improve lifespan and healthspan.

- Public and Society - benefit from the economic growth of a thriving drug development industry. Benefits will be direct, via jobs creation and access to wider and more targeted healthcare products; and indirect, via increased economic benefit of patients returning to work and increased tax revenues, that in turn feed back into the healthcare systems.


[1]. Cook. Nat Rev Drug Discov 13, 419-431 (2014).
[2]. Pammolli. Nat Rev Drug Discov 10, 428-438 (2011).
[3]. DiMasi. Health Econ 47, 20-33 (2016).
[4]. Cotovio. Altern Lab Anim 33, 329-349 (2005).
[5]. Kandarova. Altern Lab Anim 33, 351-367 (2005).
[6]. https://goo.gl/i6xbmL