Incorporation of proteinase inhibitors into silk-based delivery devices for enhanced control of degradation and drug release

Controlling the rate of silk degradation is critical to its potential use in biomedical applications, including drug delivery and tissue engineering. The effect of protease concentration on accelerating degradation, and the use of ethylenediamine tetraacetic acid (EDTA) on reducing rates of degradation and on drug release from silk-based drug carriers was studied. Increased rates of proteolysis resulted in increased dye release from silk carriers, while EDTA release from the silk carriers inhibited proteolysis. The sustained release of EDTA from silk carriers in combination with the release of the small molecule anti-convulsant adenosine was investigated in vitro. This combination of factors resulted in delayed release of adenosine by inhibiting proteolytic activity. These results introduce a promising strategy to control drug delivery through the regulation of silk degradation rate, achieved via manipulation of local proteolytic activity. This ability to modulate enzyme function could be applicable to a range of silk biomaterial formats as well as other biodegradable polymers where enzymatic functions control biomaterial degradation and drug release rates.