Development of a Multi-Modal StimulationPlatform for the 3D Culture of Wholly EdibleSkeletal Muscle Tissue

该项目福尔斯属于EPSRC再生医学创新技术研究领域，在医疗保健技术主题内。畜牧业占全球温室气体排放量的约14. 5%。随着越来越多的国家承诺到2050年实现净零碳目标，覆盖全球总排放量的88%，减少肉类生产的影响对实现这些目标至关重要。为了满足日益增长的需求，大面积的森林砍伐已经被部署。在2022年的前6个月，超过1200平方公里的巴西亚马逊地区被清理，其中36%的农业砍伐森林仅分配给牧场，这是清理土地的最大单一利用案例。这对当地的生态系统和生物多样性造成了灾难性的影响，同时也消除了全球最大的碳汇之一。此外，饲养和屠宰供人类消费的动物也带来了重大的伦理困境，每年有超过700亿只动物被杀死。解决与肉类生产相关的环境和伦理问题的方法之一是发展养殖肉类。培养肉是通过从活体动物身上取活组织切片来生产的，利用组织工程技术，这些细胞被培养成一种复制传统肉类选择的产品。Ivy Farm是该研究的前沿公司，也是该项目的工业合作伙伴。该项目提出将中空纤维膜生物反应器用于该应用。与3D生物打印替代品相比，这些为培养肉类生产提供了一个可扩展的低成本平台。此外，搅拌槽生物反应器用于大容量细胞生产，但缺乏其他生物反应器设计的分化潜力，使其不太适合复制肉类的复杂结构和质地。该项目的首要目标是设计一个中空纤维膜生物反应器平台，该平台利用完全可食用的内部结构，并需要最少的下游加工，然后才适合培养肉类产品。中空纤维膜生物反应器非常适合这种应用，因为它们有助于体内环境的复制。中空纤维充当血管的角色，用于输送营养和氧气，同时提供细胞可以接种的支架。将利用多种细胞刺激模型，如电信号，促进细胞分化，以获得所需的最终结构和纹理。将这些技术应用于养殖肉类生产是非常新颖的，将与Ivy Farm一起从头开始开发。核心步骤被视为中空纤维膜的不同材料和制造技术的评估。这些必须与一组最能代表真正动物组织性能的参数进行比较。这对培养肉也是一个独特的挑战，因为严格的生物医学应用并不需要质地和风味的改善。因此，可以开始生物反应器的设计和制造，考虑刺激方法以最好地促进分化。此外，将有一个重要的数学建模方面，使未来的设计迭代优化。基于合作者开发的质量传输模型，这些模型将应用于每个生物反应器内的特定条件，并通过实验进行验证。此外，该项目与牛津人形生物反应器实验室小组密切相关。这不仅带来了体外建模技术领域的专业知识，而且与生物医学行业有着密切的联系，这意味着可以探索新疗法开发的任何潜在应用。

This project falls within the EPSRC Innovative technologies for regenerative medicine research area, within the Healthcare Technologies Theme.ndustrial livestock farming is responsible for approximately 14.5 % of global greenhouse gas emissions.With an increasing number of nations committing to net zero carbon targets by 2050, covering 88 % of totalglobal emissions, reducing the impact of meat production is critical to meeting these aims. For productionto match the ramping demand, widespread deforestation has been deployed. In the first 6 months of 2022over 1200 square kilometers of the Brazilian Amazon were cleared, with 36 % of agricultural deforestationallotted to cattle pastures alone, the largest single utilisation case for the cleared land. This has disastrouseffects on local ecosystems and biodiversity as well as removing one of the largest global carbon sinks.Additionally, there are significant ethical dilemmas attached to the rearing and slaughter of animals forhuman consumption, with over 70 billion animals killed each year.One of the methods proposed to tackle the environmental and ethical issues associated with meat production is the development of cultured meat. Cultured meat is produced by taking a biopsy from a livinganimal and, using tissue engineering techniques, these cells are cultivated to form a product which replicates traditionally available meat options. Ivy Farm are a company at the forefront of this research andare the industrial partner for this project.This project proposes that hollow fibre membrane bioreactors are deployed for this application. Theseoffer a scalable, low-cost platform for cultured meat production when compared to 3D bioprinting alternatives. Additionally, stirred tank bioreactors are used for large volume cell production, but lack the differentiation potential of other bioreactor designs, making them less well suited to replicating the complexstructures and textures of meat.The overarching aim for the project is to design a hollow fibre membrane bioreactor platform which utilisesa wholly edible internal structure and requires minimal downstream processing before it is suitable fora cultured meat product. Hollow fibre membrane bioreactors are ideally suited to this application asthey facilitate the replication of the in-vivo environment. Hollow fibres serve the role of blood vessels for1nutrient and oxygen transport, while providing a scaffold onto which cells can be seeded.Multiple models of cell stimulation, such as electrical signalling, will be utilised to promote cell differentiation to achieve the desired final structure and texture. The application of these techniques to culturedmeat production is highly novel and will be developed from the ground up alongside Ivy Farm.The central steps are seen as the evaluation of different materials and manufacturing techniques for thehollow fibre membranes. These must be compared against a set of parameters that best represent theperformance of genuine animal tissue. This is also a unique challenge to cultured meat, as considerationsof texture and flavour are not required for strictly biomedical applications. Consequently, bioreactor designand manufacture can be commenced, factoring in stimulation methods to best facilitate differentiation.Furthermore, there will be a significant mathematical modelling aspect, enabling future design iterationsto optimised. Building on mass transport models developed by collaborators, these will be applied tothe specific conditions within each bioreactor, and validated experimentally. Additionally, this project isclosely linked to the Oxford humanoid bioreactor lab group. Not only does this bring expertise in the fieldof in-vitro modelling techniques, but also a close link to the biomedical industry, meaning any potentialapplications to novel therapy development can be explored.