Starting a new era of bioprocess development – smaller, smarter, controlled…
With the help of microbioreactors researchers can set up and analyze within a short time frame a wide variety of experiments and gain profound understanding of the studied bioprocess. Microfluidic technology brings full bioprocess control and precise dosing to micro-scale, thus parameters can be optimized at early stage. Consequently, only few confirmation runs are necessary at lab-scale before further up-scaling. This new BioLector® Pro technology paves the way for much faster R&D and the application of more advanced industrial bioprocesses.

Research based on parallel fermentation

Reducing costs while developing efficient bioprocesses as fast as possible becomes a stringent task. Intensive screening including a vast number of different experiments regarding strains, media composition and process conditions has to be conducted in order to create high yields and product titers. High-throughput fermentation in microliter scale is the method of choice as it generates high data output while cutting costs due to savings on time and workforce, automation and low material input. Whereas different solutions for milliliter scale fermentation already exist, the market still lacks powerful tools for full process control in microliter scale.
Already established in academia and industry the BioLector® system offers highly paralleled fermentations in a 48 well microtiter plate with standard SBS footprint. Utilizing the unique FlowerPlate® the system provides full online measurements of biomass, DO and pH-value, as well as up to three additional fluorescences for each individual well in 800-1500 µL working volume. Due to its special shape the FlowerPlate® can reach oxygen transfer rates (OTR) of up to 120 mmol/L/h, comparable to bench-top stirred-tank reactors. The disposable plates are delivered pre-calibrated, sterile and ready-to-use.

Proof of concept

In a recent study, this versatile tool was applied for the rapid determination of metabolic effects of a variety of oxygen transfer conditions for the cultivation of C. glutamicum (Käß et al., Bioprocess Biosyst Eng 2014, 37:1151-1162). With the oxygen transfer screening approach, metabolic effects within a broad range of supply conditions were studied in a fraction of the time required for other protocols, e.g. investigations using stirred tanks. Systematic effects on growth, productivity and side-product formation were identified and studied. Monitoring respiration activity additionally provided the relevant information for scale-up and transfer to other reactor systems. It has been proven that oxygen supply is yet another suitable development parameter during earliest bioprocess optimizations, similar to the established screening procedures for strains or media components. The use of high mixing, high gas transfer microtiter cultivation devices, such as the BioLector®, provides a suitable alternative to stirred tank or shake flask cultivations in bioprocess development. It reduces the number of required cultivations for reaching optimized operating conditions in aerobic bioprocesses, and thus boosts the efficiency of many developments in current industrial biotechnology.

Figure: The Microfluidic FlowerPlate® and the BioLector® Pro

The microfluidic principle

The next generation tool, BioLector Pro®, pushes the capabilities of microscale fermentation forward to individual full bioprocess control. The advanced system offers individually and fully controlled reactor wells with liquid pH-regulation and fed-batch possibilities. A microfluidic chip replaces the usual plate bottom allowing to pump nanoliter-amounts of liquid independently into the individual wells without losing the online-monitoring capabilities of the basic system. As the first two well rows are used as reservoirs for the desired feeding solutions, the remaining 32 wells work as distinct bioreactors. The task for each reservoir row can be chosen independently, enabling the system to deliver two different feeding solutions, one feed and one pH-value up- or down-regulation, or full pH-control for each well column. Constant, linear or exponential feeding can be chosen while a PI-controller derivate ensures proper pH-control. The microfluidic technology utilizes pressurized air to actuate membrane valves at the bottom of the microfluidic chip. The liquids are pumped through the chip via micro channels directly into the wells. The complete plate remains a closed system and can still be purchased as a disposable item. The system is operated with a proprietary software providing an user friendly interface with which experiments can be defined and supervised. The progress of 32 parallel cultivations is monitored and controlled in real-time and displayed promptly. Additionally, calibration sets of biomass concentration and optodes for DO and pH-value can easily be imported. Different analysis functions allow the evaluation and comparison of measurement data and derivatives from one or more experiment runs of 32 parallel fermentations just by a few clicks.

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