The role of transport phenomena on efficacy, stability and hysteresis in encapsulated cellular systems

Multiple steady states are possible when transport limitations are imposed on cellular systems that exhibit some level of substrate inhibition. These distinct steady states can be achieved under identical operating conditions such as temperature, flowrate, and composition. Cells will exhibit different metabolisms depending on their environmental history and the path taken to the specific reactor operating conditions. Hysteresis is observed and subsequent tracking to the alternate steady state requires significant perturbations in operating conditions. The stability of each steady state needs to be evaluated since limit cycles are a distinct possibility. Ongoing research in our laboratory using biomimetic membranes in encapsulation motifs suggests that membrane transport properties play a key role. In situations where high substrate concentrations inhibit major pathways, mass transfer resistance can beneficial effect. By ensuring low concentrations at the cellular interface, productivities can be increased. However, a practical limit to this resistance is set by the need to minimize product accumulation, and hence potential cellular toxicity. To demonstrate the role of transport properties on multiple steady state behavior, we have selected the enzymatic conversion of glucose with a transport resistance existing between the bulk fluid and the cellular surface. This system possesses key features needed to address more complicated problems presently being studied in our laboratory. One current focus area is the encapsulation of islet cells in intelligent membranes for transplantation in the treatment of diabetes. Selective transport of insulin, glucose, and other key nutrients is imperative, as is the control of T-cell and antibody attack