Local drug delivery of a matrix metalloproteinase inhibitor for endovascular stenting.

摘要

Significant occurrences of restenosis, or renarrowing within the artery, remain a complicating factor of endovascular stent implantation. Modifications of safranin O and von Kossa stains for proteoglycan and calcium salt resolution, respectively, were developed for polymethyl methacrylate-embedded stented arteries. Internal elastic lamina loss of integrity correlated to increases in proteoglycan accumulation through myointimal hyperplasia after arterial injury induced by both balloon angioplasty and endovascular stenting. The arterial hyperplastic response appears to lead to calcification that occurred within the media/neomedia, at the site of the internal elastic lamina, and in apposition to stent struts.; Due to the confirmation of cellular proliferation following arterial injury, a local drug delivery system for endovascular stents was developed in efforts to decrease this cellular proliferation. GM6001, a matrix metalloproteinase inhibitor (MMPI), was incorporated into poly(lactide-co-glycolide) (PLGA), an absorbable polymer, to produce a coating for 316L stainless steel discs. Degradation of the PLGA coating in phosphate buffered saline (PBS) resulted in an adequate release rate of GM6001, an increased lactic acid release, and the generation of hydrogen ions (decrease in pH) within the surrounding aqueous environment.; As mentioned previously, an adequate release rate of GM6001 from the PLGA coating was achieved that proved to reduce the proliferation rate of human aortic smooth muscle cells (HASMCs) in vitro by 30.7% and 37.4% as compared to the metal substrate after 4 and 7 days, respectively. However, the matrix metalloproteinase-2 (MMP-2) activity normalized to cell number was not statistically different between GM6001 coated discs and metal discs. This similarity of MMP activity represents the continued effort of the HASMCs to degrade extracellular matrix. However, the released MMP-2 is inhibited with the GM6001 resulting in the reduction of HASMC proliferation. Using a scrape wound injury method, the migration of the SMCs was shown to decrease by 21.4% with GM6001 released from the PLGA coating as compared to the metal discs. Therefore, results suggest that releasing a MMPI from an absorbable coating on 316L stainless steel provides a reduction of SMC proliferation and migration rates, while maintaining the overall production of MMPs in efforts to retain normal cellular regulation.