Miniaturisation of high throughput healthcare bioreactors for advanced therapeutics

点击翻译按钮获取中文摘要

There is little doubt of the promise of reprogramming a patient's own cells to combat degenerative diseases using cell and gene therapies (CDGT), given the success of Novartis Kymriah immunotherapy. However, one principal problem persists: the price point. The colossal costs of CGT reflect the current state-of-the-art: a slow manufacturing and development process from discovery to commercialization along with the exorbitant costs of multiple equipment needed to perform different processes. Thus, the bottleneck exists between production and accessibility. There is currently an unfulfilled need for a robust, scalable and closed bioprocessing manufacturing platform that can enable safe, low cost treatments, and rapid development time to improve accessibility to patients.Our primary goal is to develop a high-throughput bioprocessing platform based on microfluidics technology. Microfluidics - the science of fluid manipulation in the microscale - is able to address the challenges for streamlined and high-throughput cell culture production by optimizing fluid consumption during cell expansion. We have already submitted a European patent application (B74637EP D38585) of a microfluidic chip design, which is the heart of the bioprocessing platform device. This design differs from existing microfluidic work because it is multi-functional, i.e. capable of performing standard processes (seeding, transduction, washing, sampling, harvest) in situ in a sealed environment while preventing invasive interventions.Our innovation comes from the microfluidic technology applied to large scale cell culture compared to conventional 2D/3D manufacturing. The microfluidic cell culture technology has demonstrated several advantages compared to conventional methods:1. Ability to perform seeding, expansion, transduction, differentiation, filtration, sampling and harvest processes in a closed system. Conventional 2D/3D systems and even current small-scale microfluidic systems have limited functionality (i.e. conceived to perform one or a few functions, e.g. expansion and perfusion) and therefore require 'opening' the process at some point, which usually is labor-intensive (therefore costly) and poses a safety threat (e.g. contamination). 2. Dramatic reduction in reactant consumption: usually 10-20x lower reactant consumption due to inherent minute volumes coupled with continuous perfusion systems used in microfluidics. Currently, with conventional 2D/3D systems, reactants represent 30-35% of total costs.3. Better control of process parameters. 2D/3D systems are characterized by high cell to total volume ratio which leads to heterogeneous end product and low process efficiency (e.g., 1-2 days to transduce cells). Microfluidics allows to finely control concentrations and maximize cell-to-reactant contact, i.e. cells have equal access to oxygen and nutrients due to fluid circulation in micro-channels, which results in a more homogeneous end product and less process failure (e.g. cell death). 4. Ability to scale up without process change. Scale-ups with conventional 2D/3D technology require process adaptation. Existing small-scale microfluidic systems are not designed for high-throughput and thus cannot be scaled in a cost-effective way. Our platform uses a stackable cassette system which can be scaled from a few hundred cells to several hundred million of cells, without any process adaptations. Cells and fluids can be transferred between different parts of the system via automated pumps and microfluidic valves.The invention of a bioprocessing platform that responds to these specifications requires multi-disciplinary approach and understanding of the underlying scientific principles: flow hydrodynamics (fluid mechanics), cell growth and culture (biology/biophysics/biochemistry), together with the development of the hardware (engineering) used for parallelization and automation of multiple large chips.