BACKGROUND: In recent years, biochemical and biotechnological engineering has been applied to the culture of human and animal tissue cells, which requires the design, operation and control of complex bioreactors. Hollow fibre membrane bioreactors provide favourable conditions for cellular function and metabolism. To develop bioartificial systems ensuring stable and long-term operation, fluid dynamics and transport phenomena require careful automation strategies. RESULTS: Starting from a crossed hollow-fiber membrane bioreactor for the culture of complex cell systems configured to operate manually, a 2 x 2 liquid level/flow-rate control system is experimentally developed and thoroughly tested for its robustness against liquid level or flow-rate set-point changes and disturbances arising from loop interaction. The automation system is shown to be fast for flow-rate and sufficiently reliable for liquid level (response times of minutes). Limitations are mostly owing to flow-rate difference constraints and level sensor noise, both originating from cell culture requirements. Prolonged operation (27 days) of the bioreactor in maintaining human hepatocytes in a three-cell co-culture system is presented and discussed. CONCLUSION: The results shown in the present work allow improving the understanding of the dynamic behaviour of a membrane bioreactor for biomedical application and examining the possibility to run the bioreactor under fully automated pre-set conditions smoothly and for extended periods of time. (C) 2017 Society of Chemical Industry