The impact of monomer sequence and stereochemistry on the bulk properties of repeating sequence poly(lactic-co-glycolic acid) matrices

摘要

Poly(lactic-co-glycolic acid) (PLGA)-based biodegradable materials have attracted considerable interest in the field of bioengineering due to their biocompatibility, FDA approval and tunable physico-chemical properties. Current methods for tuning the properties of PLGAs for a specific therapeutic application are, however, limited to changing the monomeric ratio and stereochemistry of cyclic diesters prior to ring-opening polymerization (ROP), a reaction that produces an unsequenced random copolymer. To understand how sequence, both structural and stereochemical, can be exploited to tune PLGA properties for specific applications, copolymers bearing periodic repeating sequences of lactic and glycolic acid were prepared using segmer assembly polymerization (SAP), an approach for controlling the sequence and stereochemistry within PLGA. A series of sequenced PLGAs were prepared, fabricated into various therapeutic devices, and characterized both in their initial states and after exposure to physiological conditions to promote hydrolytic degradation. Changes in sequence, stereochemistry, and monomeric ratios were shown to have a profound effect on such properties as in vitro erosion, swelling, compressive modulus, ultimate compressive stress, internal morphology, and crystallinity in implantable pellets. Data acquired from thermal analysis, gel permeation chromatography, and proton nuclear magnetic resonance established that the onset of molecular weight loss and oligomer formation via hydrolytic cleavage may be delayed based on backbone sequence. Two-photon microscopy studies of PLGA microparticles dramatically illustrate the profound influence of backbone sequence on the hydrolysis profile and development of the internal acidic microclimate. Sequenced PLGA microparticles were found to maintain their initial internal pH over a 28 d time period compared to their random analogues. These results were confirmed by evaluating the in vivo foreign body response to subcutaneous microparticle injections. After 28 d in vivo, the alternating stereopure PLGA, poly LG, had minimal giant cell infiltrate compared to the commonly used random analogue, PDLGA-50. These discoveries establish a greater understanding of the role of sequence in controlling properties for bioengineering applications in addition to providing valuable insight into the preferential hydrolysis mechanism of sequenced PLGAs.