Improved Biocompatibility of Poly(lactic-co-glycolic acid) and Poly-L-Lactic Acid Blended with Nanoparticulate Amorphous Calcium Phosphate in Vascular Stent Applications

Abstract

Biodegradable polymers used as vascular stent coatings and stent platforms encounter a major challenge: biocompatibility in vivo, which plays an important role in in-stent restenosis (ISR). Co-formulating amorphous calcium phosphate (ACP) into poly(lactic-co-glycolic acid) (PLGA) or poly-L-lactic acid (PLLA) was investigated to address the issue. For stent coating applications, metal stents were coated with polyethylene-co-vinyl acetate/poly-n-butyl methacrylate (PEVA/PBMA), PLGA or PLGA/ACP composites, and implanted into rat aortas for one and three months. Comparing with both PEVA/PBMA and PLGA groups after one month, the results showed that stents coated with PLGA/ACP had significantly reduced restenosis (PLGA/ACP vs. PEVA/PBMA vs. PLGA: 21.24 +/- 2.59% vs. 27.54 +/- 1.19% vs. 32.12 +/- 3.93%, P < 0.05), reduced inflammation (1.25 +/- 0.35 vs. 1.77 +/- 0.38 vs. 2.30 +/- 0.21, P < 0.05) and increased speed of re-endothelialization (1.78 +/- 0.46 vs. 1.17 +/- 0.18 vs. 1.20 +/- 0.18, P < 0.05). After three months, the PLGA/ACP group still displayed lower inflammation score (1.33 +/- 0.33 vs. 2.27 +/- 0.55, P < 0.05) and higher endothelial scores (2.33 +/- 0.33 vs. 1.20 +/- 0.18, P < 0.05) as compared with the PEVA/PBMA group. Moreover, for stent platform applications, PLLA/ACP stent tube significantly reduced the inflammatory cells infiltration in the vessel walls of rabbit iliac arteries relative to their PLLA cohort (NF-kappaB-positive cells: 23.31 +/- 2.33/mm2 vs. 9.34 +/- 1.35/mm2, P < 0.05). No systemic biochemical or pathological evidence of toxicity was found in either PLGA/ACP or PLLA/ACP. The co-formulation of ACP into PLGA and PLLA resulted in improved biocompatibility without systemic toxicity.

Novel Biodegradable Drug-Eluting Stent Composed of Poly-L-Lactic Acid and Amorphous Calcium Phosphate Nanoparticles Demonstrates Improved Structural and Functional Performance for Coronary Artery Disease

“…Moreover, it offers excellent bioactivity (low/no cytotoxicity) and the ability to neutralize acidic metabolites resulted from hydrolytic degradation of PLLA. 13 In our earlier studies, 14 ACP was demonstrated to significantly increase the biocompatibility of PLGA as a stent coating layer in a rat aorta stenting model. The metal stents coated with PLGA/ACP composite expedited reendothelialization process, helping endothelial cell migration to cover the injured rat arterial wall.…”

“…Each stent was then surface-coated with a layer of paclitaxel in PLGA/ACP (∼ 20 m thickness) as described in our previous report. 14 15 Paclitaxel doses in-strut and on-surface for both stents were presented in Table I. By design, paclitaxel was released from the surface and from within the PowerStent ® Absorb as a function of biodegradation.…”

“…21 The released P 2 O 4− 7 ion would then be hydrolyzed in aqueous fluid, forming hydroxide ions (OH − . Finally, the hydroxide ions (OH − ) would neutralize any carboxylic acid end group available upon PLLA degradation, 14 and thus reduce inflammation occurrence. 22 In addition, calcium ions could be immobilized with end chain carboxylic acid groups to form insoluble salts, or complexed with carboxylic acids, providing another possible mean of acid removal.…”

6-Month Follow-Up of a Novel Biodegradable Drug-Eluting Stent Composed of Poly-L-Lactic Acid and Amorphous Calcium Phosphate Nanoparticles in Porcine Coronary Artery

“…As discussed previously, the possible mechanisms of ACP-related increase in PLLA's mechanical properties include restricting its chain mobility, promoting its dimensional stability and increasing the PLLA/ACP composite crystallinity during the degradation process. [14][15][16][17] Since the radial strength is a function of the polymer molecular weight and crystallinity, 27 28 a stent with increased crystallinity would be predicted to have a greater radial strength. In addition, the stent was designed as a unique dual ring structure which also helps to improve radial strength.…”

“…[14][15][16][17][18] Our most recent study in porcine coronary artery also demonstrated that the stent had increased structural stability and excellent antirestenotic property one month post-implantation. 19 In the present study, we further evaluate this novel biodegradable DES with respect to the radial strength, biocompatibility and functionality in a porcine model of coronary artery stenting with 6-month follow-up results available.…”