Pharmacological modulation of the tissue response to implanted polylactic-co-glycolic acid microspheres

Polylactide microspheres have been identified as a promising release system for the sustained delivery of protein therapeutics. We prepared microspheres (30-50 microns) from either polylactic acid monomers (PLA), polytactic-co-glycolic acid (PLGA) monomers containing 12-carbon end groups (blocked PLGA, B-PLGA) or unmodified polylactic-co-glycolic acid monomers (unblocked PLGA, UB-PLGA) and injected these subcutaneously into the interscapular region of rats. Striking differences were observed in the cellular and fibrotic responses to these polymers monitored at various times over a 30 day time course. Incorporation of recombinant human insulin-like growth factor-I (rhIGF-I) into B- and UB-PLGA microspheres at a loading of 14.8 and 15.5%, respectively, did not alter the tissue response to these polymers. Infusion of various agents intended to pharmacologically modify cellular and fibrotic events associated with the tissue response demonstrated that such a manipulation was possible. Together our results demonstrate that the inherent physical and chemical properties of PLA, B-PLGA and UB-PLGA dictate biological aspects of the tissue response to a large extent but open the possibility of modulating these tissue response events through pharmacological intervention.