Development of poly(D,L-lactic-co-glycolic acid) films coated with biomembrane-mimicking polymers for anti-adhesion activity.

A physical barrier is one of the most effective strategies to alleviate excessive postoperative adhesion (POA) between tissues at an injury site. To overcome the limitations of current polymeric film-type physical barriers, we suggest a film of poly(lactic-co-glycolic acid) (PLGA) that is non-covalently coated with poly(2-methacryloyloxyethyl phosphorylcholine (MPC)-co-n-butyl methacrylate (BMA)) (PMB). While maintaining the degradability and mechanical properties of PLGA, the PMB coating introduces strong anti-adhesive properties to the film by forming a zwitterionic MPC-based surface through the hydrophobic interactions between BMA moieties and PLGA. Compared to SurgiWrap®, the commercially available poly(lactic acid)-based anti-adhesive film against POA, the PMB-coated PLGA film is much more inhibitory against protein adsorption and fibroblast adhesion, processes that are crucial to the POA process. PMB coating also inhibits the expression of fibronectin containing extra domain A (FN-EDA), α-smooth muscle actin (α-SMA), and collagen type IV alpha 2 (COL4A2), which are marker genes and proteins involved in fibroblast activation and excessive fibrosis during POA. Such inhibitory activities are clearly observed in a 3-dimensional culture of fibroblasts within a collagen matrix, which mimics the in vivo environment of an injury site, as well as in a 2-dimensional culture. The kinetics and the stability of the PMB coating suggest potential future clinical use to coat PLGA films to create a film-type anti-adhesion barrier that overcomes the limitations of current products.

Paclitaxel coating on the terminal portion of hemodialysis grafts effectively suppresses neointimal hyperplasia in a porcine model.

OBJECTIVE: The local delivery of paclitaxel onto a graft has been reported to prevent neointimal hyperplasia. Because more than half of vascular stenoses occur within 3 cm of the venous anastomosis, this study tested the effectiveness of a paclitaxel coating restricted to both ends of the expanded polytetrafluoroethylene (ePTFE) graft to reduce the amount of drug delivered. METHODS: Both ends of ePTFE grafts were coated with paclitaxel at a dose of 0.58 µg/mm(2); the total amount of paclitaxel per graft was 0.66 mg. Paclitaxel-coated hemodialysis grafts 15 cm in length were surgically implanted between the common carotid artery and external jugular vein in female Landrace pigs. The animals were sacrificed 6 weeks after graft placement. Cross sections of the anastomosis sites were analyzed histomorphometrically to measure the ratio of neointimal hyperplasia to the graft area (H/G ratio) and the percentage of luminal stenosis. The experimental results were compared between grafts coated with paclitaxel at the ends only (n = 8), grafts coated over the entire length (n = 6), and uncoated control grafts (n = 6). RESULTS: The mean ± standard error values of the H/G ratios for the arterial anastomosis were 0.82 ± 0.13 (control), 0.41 ± 0.09 (terminal coating), and 0.21 ± 0.04 (whole coating). The values for the venous anastomosis were 0.82 ± 0.12 (control), 0.39 ± 0.11 (terminal coating), and 0.12 ± 0.03 (whole coating). Compared with the uncoated grafts, neointimal hyperplasia was suppressed effectively in the vascular grafts coated terminally with paclitaxel (artery, P = 050; vein, P < .001). However, the suppressive effect was less than that of grafts coated with paclitaxel over the entire length. The percentages of luminal stenosis showed similar tendency to the H/G ratios. CONCLUSIONS: Despite a reduced amount of the drug, paclitaxel coating applied to both ends of the ePTFE hemodialysis grafts effectively suppressed neointimal hyperplasia at the sites of anastomosis.

Paclitaxel coating of the luminal surface of hemodialysis grafts with effective suppression of neointimal hyperplasia.

OBJECTIVES: Paclitaxel coating of hemodialysis grafts is effective in suppressing neointimal hyperplasia in the graft and vascular anastomosis sites. However, paclitaxel can have unwanted effects on the surrounding tissues. To reduce such problems, we developed a method to coat the drug only on the luminal surface of the graft, with little loading on the outer surface. METHODS: A peristaltic pump and a double-solvent (water and acetone) system were used to achieve an inner coating of paclitaxel. At the ratio of 90% acetone, paclitaxel was homogeneously coated only on the luminal surface of the graft without changing the physical properties. To determine its effect, grafts were implanted between the common carotid artery and the external jugular vein in pigs using uncoated control grafts (n = 6) and low-dose (n = 6, 0.22 µg/mm(2)) and high-dose (n = 6, 0.69 µg/mm(2)) paclitaxel inner-coated grafts. Cross-sections of graft-venous anastomoses were analyzed histomorphometrically 6 weeks after placement to measure the patency rate, percentage of luminal stenosis, and neointimal area. RESULTS: No signs of infection or bacterial contamination were observed in the paclitaxel inner-coated groups. Only one of the six control grafts was patent, but all of the paclitaxel-coated grafts were patent, with little neointima. The mean ± standard error values of percentage luminal stenosis were 75.7% ± 12.7% (control), 17.5% ± 3.1% (low dose), and 19.7% ± 3.0% (high dose). The values for the neointimal area (in mm(2)) were 8.77 ± 1.66 (control), 3.53 ± 0.73 (lose dose), and 4.24 ± 0.99 (high dose). Compared with the control group, paclitaxel inner-coated vascular grafts significantly suppressed neointimal hyperplasia (low dose, P = .001; high dose, P = .002). Myofibroblast proliferation and migration into the graft interstices confirmed the firm attachment of the implanted graft to the surrounding tissue. CONCLUSIONS: Paclitaxel coating on the inner luminal surface of vascular grafts was effective in suppressing neointimal hyperplasia, with little inhibition of myofibroblast infiltration within the graft wall.

Suppression of neointimal hyperplasia by sirolimus-eluting expanded polytetrafluoroethylene (ePTFE) haemodialysis grafts in comparison with paclitaxel-coated grafts.

BACKGROUND: Haemodialysis vascular access dysfunction caused by aggressive venous neointimal hyperplasia is a major problem for haemodialysis patients with synthetic arteriovenous (AV) grafts. Several different strategies to prevent venous stenosis by inhibiting smooth muscle cell proliferation and migration using local delivery of potent antiproliferative agents are currently under investigation. We performed this study to evaluate the efficacy of sirolimus-eluting vascular grafts in preventing stenosis and to compare the effectiveness of sirolimus-coated grafts with that of paclitaxel-coated vascular grafts that we characterized in a previous study. METHODS: AV grafts were implanted laterally between the common carotid artery and external jugular vein of 14 female Landrace pigs. Three types of grafts were implanted: grafts coated with 1.08 µg/mm(2) sirolimus (low dose, n = 6), grafts coated with 2.41 µg/mm(2) sirolimus (high dose, n = 2) and uncoated control grafts (n = 6). Animals were sacrificed 6 weeks after surgery. Cross-sections of the venous anastomoses were analysed to determine the percentage of luminal stenosis in each group, and immunohistochemistry was performed to identify the cellular phenotypes of the neointimal hyperplasia and tissues adjacent to the implanted grafts. RESULTS: Compared with the control group, neointimal hyperplasia in the venous anastomoses of the groups implanted with sirolimus-coated vascular grafts was significantly suppressed without infection. The mean ± standard error values for the percentage of luminal stenosis were 75.7 ± 12.7% in the control group and 22.2 ± 1.41% in the low-dose sirolimus-coated group. Myofibroblasts and fibroblasts were the major cell types found in the neointimal hyperplasia. CONCLUSIONS: Neointimal hyperplasia was effectively suppressed by sirolimus-eluting grafts. However, the inhibitory effects of sirolimus-eluting grafts were weaker than those observed for paclitaxel-coated grafts in our previous study.