Controlled release of bioactive substances requires that the encapsulated material retain its bio logical activity or the activity of acceptable degradation products. Encapsulation of these mol ecules is commonly performed not only to retain and/or to slowly release them, but to provide a more stable environment for the encapsulated species. For example, encapsulation of enzymes within a support material containing fixed ionogenic groups (e.g., ion exchangers) can provide an optimal microenvironmental pH for stability by altering the partitioning of H+ (1). However, in certain instances the microclimate within the matrix is more destabilizing than if the sub stance were not encapsulated at all. Such has been found for some substances encapsulated in poly(lactide-co-glycolide) (PLGA). For example, a commonly observed phenomenon of pro teins encapsulated in PLGA is that during release the protein ceases to come out of the polymer (e.g., entrapment due to aggregation), or once released the protein is devoid of biological activ ity. An additional problem concerns destabilization of the substance during encapsulation. Since PLGA is a particularly important biodegradable polymer to deliver drugs for periods exceeding 1-3 months (2,3), the task of optimizing the encapsulated molecule in an apparently deleterious environment becomes a critical obstacle to overcome. Herein we will describe our approach to examining the stability of encapsulated substances in PLGA as well as our important findings on this topic to date.