Multi-Compartmental Modular Bioreactor as Innovative System for Dynamic Cell Cultures and Co-Cultures

In this chapter, the design, fabrication process and preliminary tests of a Multi- Compartmental Modular Bioreactor used as a system for dynamic cell cultures and co-cultures is described. Although the microwell (MW) plate has become a standard in cell culture, the complexity of the physiological environment is not replicated in petri dishes or microplates. All cells are exquisitely sensitive to their micro-environment which is rich with cues from other cells and from mechanical stimuli due to flow, perfusion and movement. Microwells do not offer any form of dynamic chemical or physical stimulus to cells, such as concentration gradients, flow, pressure or mechanical stress. This is a major limitation in experiments investigating cellular responses in-vitro since the complex interplay of mechanical and biochemical factors is absent. Most researchers and industry have started to accept that classical in vitro experiments offer poor predictive value or mechanistic understanding and are shifting their interests to new technologies such as bioreactors. For this reason, a large number of bioreactor systems for cell culture have been recently designed and described. With the purpose of developing cell culture models to establish a physiological-like interaction between different cell types, a novel Multi-Compartmental Modular Bioreactor (MCmB)was realized. The modular chamber was designed with shape and dimensions similar to the 24-MultiWell allowing an easy transfer of microwell protocols. The MCmB consists of a cell culture chamber made of bio-compatible silicon polymer, with excellent self-sealing proprieties, transparency and flexibility. The modular chambers can be also connected together in series or in parallel as desired, in order to allow cell-cell cross-talk or replicate in vitro models of metabolism or diseases using allometric design principles. In this chapter we describe the bioreactor design process starting from a finite-element method (FEM) model, developed in order to study the shear stress and the oxygen concentration at the cell surface. A further version of the MCmB is also described, in which a semipermeable membrane is placed into the bioreactor allowing to create a double-chamber system (MCmB-dc) for biological barriers simulation like for example lung or intestine. Allometric methods for designing in-vitro organ models using combinations of different cell types or tissues cultured in different chambers are also presented. Allometric laws mathematically correlate non linear quantities such as organ mass, blood flow, blood retention time and metabolic rate. Using these laws the modules can be assembled in various configurations enabling organ and system physiology to be recapitulated in vitro. Preliminary experiments using the modules are also described.