Bio-instructive electrospun scaffolds based on the combination of synthetic i.e, aliphatic polyesters such as PCL or PLLA – and natural polymers (i.e, collagen) have been extensively investigated as temporary extracellular matrix (ECM) analogue able to support cell proliferation and stem cell differentiation for the regeneration of several tissues [1-3]. In this context, the growing use of natural polymers as carrier of bioactive molecules is introducing new ideas for the design of polymeric drug delivery systems based on electrospun fibers with improved bioavailability, therapeutic efficacy and programmed release of drugs. In particular, the mechanism of release is driven by the use of water soluble proteins (i.e, collagen, gelatin) which fully degrade in “in vitro” microenvironment, so delivering the active principles. However, these protein are generally rapidly digested by enzymes (i.e., collagenase) produced by many different cell types, both in vivo and in vitro with significant drawbacks in tissue engineering and controlled drug delivery. Here, we aim at investigating different chemical strategies to improve the in vitro stability and mechanical strength of scaffolds against enzymatic degradation, by modifying the biodegradation rates of proteins embedded in bicomponent fibers. By the comparison of scaffolds treated by different crosslinking agents (i.e, GC, EDC, BDDGE), we have provided an extensive morphological/chemical/physical characterization via SEM/DSC/TGA to identify the best conditions to control drug release via protein degradation from bicomponent fibers without compromising in vitro cell response. References 1.Alvarez et al., Biomacromol 2010, 11(9): 2238; 2.Guarino et al, Macromol Biosci 2011, 11(12): 1693; 3.Cirillo et al Biomaterials 2014, 35(32):8970-82 Acknowledgements: POLIFARMA (PON02_3203241)and NEWTON (FIRB-RBAP11BYNP), REPAIR (PON01-02342).