Nanofibrillar cellulose as a naturally biocompatible scaffold material is very promising for tissue engineering. It is shear thinning but has the downside of not being degradable in animals, it can only be degraded by cellulase enzymes. In this study, a newly developed bioreactor was used to culture fibroblast spheroids under flow conditions inside nanocellulose hydrogels with and without the presence of cellulase. The aim was to control the tissue size and ideally find a match between degradation and tissue formation within this promising material. Both the concentration of cellulase and the flow rate were varied and their influence on the activity and growth of fibroblast clusters was assessed. Cluster diameters, degradation, metabolic activity, and tissue production increase with higher cellulase concentration, although concentrations above 1 g/l does not have an additional benefit. Flow leads to more viable cells, more proliferation and migration, leading to overall larger tissue constructs compared to static conditions. This is most likely due to the shear thinning effect of flow on cellulose nanofibrils (CNFs) in addition to the increased nutrient supply through perfusion. At a constant cellulase concentration of 1 g/l, a flow of 2 ml/min proved to be optimal for tissue production. Therefore, degradation in combination with flow leads to more effective tissue production in CNF hydrogels, which is a very potent scaffold material for tissue engineering.