Airlift Reactors

General

In addition to STRs, airlift reactors are widely used for suspension cell culture. The largest published scale of airlifts applied for animal cell culture is 2 m3, which is routinely used for monoclonal antibody production at LONZA (46,162). This relatively new bioreactor type has been scaled-up to 1500 m3 for microbial fermentation and 17,000 m3 for wastewater treatment (163) demonstrating its enormous scale-up potential. There are several publications on the use of this bioreactor type for suspension growth of mammalian (hybridoma, BHK, CHO, Namalva) (122,164-166) and insect cell lines (167). Even studies on microcarrier cell culture were reported (168,169) although it has generally been considered impractical due to microcarrier aggregation at the air-medium interface (70). Airlifts can be regarded as a type of bubble column since mixing is provided by the introduction of gas bubbles at the base of a tall column (170). In bubble columns the ascending bubbles cause random mixing. In airlifts, fluid circulation is obtained by mechanical separation of a channel for gas/liquid up-flow (riser) and a channel for down-flow (downcomer). These channels are connected at the top and the bottom of the column forming a closed loop. Fluid flow is driven by the density difference between the sparged fluid in the riser and the bubble-free fluid in the downcomer. Basically, two different geometric configurations can be distinguished: (a) external loop vessels where the circulation takes place through an external loop and (b) baffled vessels with either a cylindrical draft tube or a simple baffle resulting in an internal loop circulation (see Fig. 5). In airlifts mixing and oxygen transfer are generally coupled, i.e., the gas flow rate is controlled by the oxygen demand of the culture and determines the hydrodynamic conditions in the bioreactor. In order to decouple mixing and oxygen transfer, pH and ^O2 can be controlled by varying the composition of a carrier gas (air or nitrogen) regarding oxygen and CO2 at a maintained total gas flow rate. Typical superficial gas velocities are in the range of 0.001-0.01 m/s (67) and corresponding kIa values of 0.7-20 h_1 were reported (46).

Major design considerations are geometrical configuration of the riser and downcomer, aspect ratio, sparger layout, positions for electrodes, sample ports, feed and base addition. The most widely used design for animal cell culture is a bubble column with a concentrical draft tube. Typical aspect ratios are in the range of 6:1 to 12:1 (67,162,171). Optimum mixing is obtained by keeping the cross-sectional area of the downcomer similar to that of the riser. It has also been shown that the cylindrical area below and above the draft tube is affecting mixing. A recent review of the design and scale-up of airlift bioreactors was given by Varley and Birch (46); a comprehensive description of the engineering principle can be found in Ref. (163).

The main advantage quoted for airlift over STRs beside its ease of scale-up is that no moving parts and mechanical seals are needed which improves the reliability

Figure 5 Airlift reactor configurations. [Reprinted from Ref. (170), Copyright © 1990, with permission from Elsevier Science Publishers.]

of sterile operation (162,170). Despite these advantages the airlift is not as widely used and modified for cell culture as the STR. This has historical reasons but might also be due to the limited flexibility in terms of working volumes and suitability for microcarrier culture. Another advantage frequently quoted is its gentler mixing action and suitability for shear-sensitive cells (170). However, similar considerations as described for direct sparging in stirred tank reactors are valid for cell damage and CO2 accumulation (65).

A number of authors have studied the shear sensitivity of different cell lines such as hybridomas, BHK and insect cells in airlift and bubble column bioreactors and the effect of serum or surfactant concentration, sparger design, bubble size, and column height on cell survival (117,167,172-174). Although most reports on the use of airlift bioreactors are based on batch culture, it is generally possible to operate the system at high cell densities using external cell retention systems similar to those described for STRs. For example, Hulscher (122) used an external settler for the selective recycle of viable cells to an airlift loop reactor. Integrated perfusion devices on the basis of settling zones in external-loop airlifts are described in Ref. (175).

Modifications

A modification of the bubble column principle is the inclined plate bioreactor (176) designed to reduce the effect of bursting bubbles on cells. The inclination of the column leaves the bulk of the liquid bubble free while still providing effective liquid circulation. Another design modification to minimize cell damage due to sparging (74)

is provided in the bubble bed bioreactor (177). In this stirred tank-bubble column hybrid bioreactor the residence time of bubbles was dramatically prolonged by floating the bubbles in a countercurrent flow produced by an impeller in the lower part of a central conical draft tube.

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