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Stirred tank performance in a microbioreactor

Microbioreactor technology was initially developed in Professor Rajeev Ram's laboratory at MIT. Since the project began, technological innovations have enabled microfluidic batch and continuous cultures with online monitoring of pH, dissolved oxygen, and optical density.

Microbioreactor technology enables customizable small scale automated cell culture devices the size of a deck of cards, but with performance and functionality similar to stirred tank bioreactors.  With microbioreactors, customized devices to implement fed-batch processes and continuous cultures can be automated with the potential for parallelization.  However, commercialization of microbioreactor technology has been held back because the supporting equipment to provide control signals and read sensors has not been manufacturable or scalable.

How do Pharyx Microbioreactors work?

Pharyx Microbioreactors are made by a unique fabrication process that integrates active silicone microfluidics inside plastic devices. These structures enable on-chip reservoirs, mixers, valves, and pumps to be integrated directly on the disposable device at milliliter volumes. By running various sequential operations, fluid injection, mixing, cell removal, and perfusion output removal can all be automated.

The growth chamber consists of three interconnected chambers. Each chamber contains a fluid chamber and a gas chamber separated by a silicone membrane. By delivering pressurized gas to the gas chamber, the fluid underneath is pushed from the pressurizing chamber into the other two connected chambers. Pressurizing in a sequence generates circulating flow and mixes the fluid.

The animation below shows the typical operations performed in the microbioreactor. Only two interconnected chambers are shown for simplicity.

Gas delivery

Since the membrane separating the fluid and gas sections of each chamber is made of silicone, the pressurization process also results in significant diffusion of the pressurizing gas, generating bubble free gas delivery during mixing (Patent US7367550 B2). By simply varying the composition of the pressurization gas, oxygen and CO2 inside the growth chamber can be easily controlled.

Mixing Performance

Below we show a demonstration of real time mixing performance of the microbioreactor. Homogeneous mixing can be achieved in just a few seconds.

Sensor Integration

The flat form factor and optical clarity of the device allows for the integration of fluorescent pH and oxygen sensors seen in many other microbioreactors. Since mixing and gas delivery occur through diffusion and are bubble free, Pharyx has also developed a unique online sensor for real time optical density measurements. (Patent US9176060 B2)

Fully Disposable Fluid Path

Pharyx's multiport asceptic fluid connector (Patent Pending 62221044) enables the entire fluid path from media bottles to output waste to be sterile and disposable. The microbioreactor device is connected to the fluid bottles with a single two part connector simultaneously connecting 8 tube connections in one unit operation. Sterility is maintained with tape tabs covering the connectors. All gassing and actuation occur through a silicone membrane, ensuring that no wetted components ever contact any mechanical or electrical parts.