Making Quasi Vivo®
The Quasi Vivo® system is an advanced interconnected cell culture flow system which has been engineered to provide in vivo like conditions for cell culture.
CELL REQUIREMENTS
Traditional, static, in vitro systems do not take into consideration all the stimuli which act on cells in the human body, such as the biochemical signals from other cells, the physical and structural stimuli from the 3D microenvironment and the physico-chemical fluxes which originate from temperature, concentration or momentum gradients. Quasi-Vivo® was designed with these in mind to better replicate the physiological conditions in the body.
Initially, Quasi-Vivo® was developed using hepatocytes as a reference as they are a limiting cell type within in vitro research, due to their rapid loss of phenotype expression in the absence of an appropriate, physiologically relevant environment.
OPTIMUM CONDITIONS FOR CELLS
Hepatocytes are sensitive to oxygen concentration, due to their high metabolic demands, and are also sensitive to shear stress, with high shear stresses resulting in decreased viability of hepatocytes.
The Quasi-Vivo® milli-fluidic technology was engineered to:
- minimise shear stress on cells
- maintain high flow rates
- provide sufficient oxygen
- ensure laminar flow
- remove air bubbles
OPTIMISING OXYGEN DELIVERY
Typical oxygen concentrations range from 0.04mM to 0.10mM in the liver, with hepatocyte function compromised at 0.02mM. Micro-fluidic devices are advertised as mimicking the physiological environment however the media in the channels requires a very slow flow rate to avoid exerting high shear stresses on cells which affects oxygen concentration.
A finite-element modelling (FEM) model of chambers was developed to study oxygen concentration and shear stress at the cell culture surface. Fluid dynamic and mass transport models were used to analyse the system. Michaelis-Menten (MM) kinetics was used to model oxygen consumption and Fick’s laws were used to model oxygen diffusion in water.
The graph shows the theoretical oxygen concentration profile across the chamber for different heights, calculated using Michaelis-Menten kinetics and a flow rate of 180 μl/min. This illustrates that the oxygen concentration in the chamber is always higher than the minimal threshold and falls rapidly at the edges of the chamber near the outlet. Cell survival is always guaranteed in the central region of the chamber.
Micro-fluidic vs Milli-fluidic
This figure shows the oxygen concentration profiles in micro-fluidic systems, milli-fluidic systems and the earlier designs of Quasi-Vivo® (known as the Multi-Compartmental modular Bioreactor, MCmB) considering either oxygen impermeable or oxygen permeable PDMS walls.
The necrotic areas in the MCmB chamber were shown to be significantly lower than in the other systems. The figure also shows that the MCmB chamber is preferable as it enables adequate oxygen delivery with an acceptable level of shear stress exerted on cells.
REMOVAL OF AIR BUBBLES
The presence of air bubbles inducing a turbulent environment in micro-fluidic devices is a common problem however Quasi-Vivo® has been carefully engineered to overcome this. The design, consisting of a patented feature of the top surface being sloped, along and perpendicular to the axis, enables bubbles to be collected and conveyed to the outlet tube. The outlet tube is positioned higher than the inlet tube and has an increased diameter to facilitate the removal of bubbles.
PAPERS
For more information on the engineering behind the Quasi-Vivo® system take a look at these published papers.
Design Criteria for Generating Physiologically Relevant In Vitro Models in Bioreactors.
Authors: Mattei, G., Giusti, S. & Ahluwalia, A., 2014
Journal: Processes, 2, pp.548–569.
A Low Shear Stress Modular Bioreactor for Connected Cell Culture under High Flow Rates
Authors: Mazzei D., Guzzardi M.A., Giusti, S. & Ahluwalia, A., 2010
Journal: Biotechnology and Bioengineering
DESIGN
The Quasi-Vivo® system is based on the dimensions of a classic 24-MW to directly compare static and dynamic cell cultures in equal sized chambers. The final dimensions of the chambers were the best compromise between shear stress, flow, oxygen diffusion and mechanical feasibility. The chamber is composed of two separate parts which fit together to form a watertight seal. The chambers are made from oxygen permeable polydimethylsiloxane (PDMS) to allow for oxygen diffusion.
PRODUCTS
Quasi-Vivo® is a sophisticated and user friendly in vitro research tool that has been engineered to provide optimum conditions for cells. The Quasi Vivo® system has 3 different chambers available, each of these have been designed to meet the needs of specific applications.
Allows for submerged cell culture, whilst the modular nature allows for interconnecting cell co-culture.
Compatible with commercially available transwells and inserts, giving users the ability to culture cells at the air liquid interface and create liquid/liquid barrier models.
Consists of 6 chambers on a standard multi-well plate footprint and is made from a material with little to none non-specific binding.
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