Propylthiouracil-coated biodegradable polymer inhibited neointimal formation and enhanced re-endothelialization after vascular injury.

BACKGROUND: The drug-eluting stent is a standard approach for the treatment of coronary artery disease. Propylthiouracil (PTU), an antithyroid drug, has been proven to suppress neointimal formation after balloon injury. MATERIALS AND METHODS: This study used a biodegradable polymer coating with PTU to test its effects on platelet function, re-endothelialization, and neointimal formation after vascular injury. Electrospinning was used to fabricate hybrid stents and generate PTU-loaded nanofibers. RESULTS: PTU-eluting stents maintained a stable release of PTU for 3 weeks. The PTU-coated stent markedly decreased the neointimal formation induced by vascular injury in the descending aorta of rabbits. Moreover, the PTU coating reduced platelet adhesion on the surface of the biodegradable membrane, which was reflected by the decreased expression of adhesion molecule in PTU-treated endothelial cells. The PTU coating enhanced re-endothelialization in injured aortas. In vitro, PTU exerted less suppressive effect on the proliferation and migration of endothelial cells than on those of vascular smooth muscle cells. Furthermore, treatment of endothelial cells with PTU induced phosphorylation (Ser1177) of endothelial nitric oxide synthase as well as its association with heat shock protein 90, supporting the protective role of PTU in endothelial function. The level of thyroid-stimulating hormone remained unchanged during the experimental period. CONCLUSION: This study indicates that PTU can be released locally and steadily in injured aortas, with some local effects but without systemic effects. Furthermore, PTU-coated stents may have beneficial effects on neointimal formation, endothelial cell, and platelet functions.

Biodegradable Cable-Tie Rapamycin-eluting Stents.

"Cable-tie" type biodegradable stents with drug-eluting nanofiber were developed to treat rabbit denuded arteries in this study. Biodegradable stents were fabricated using poly-L-lactide film following being cut and rolled into a cable-tie type stent. Additionally, drug-eluting biodegradable nanofiber tubes were electrospun from a solution containing poly (lactic-co-glycolic acid), rapamycin, and hexafluoroisopropanol, and then mounted onto the stents. The fabricated rapamycin-eluting cable-tie stents exhibited excellent mechanical properties on evaluation of compression test and collapse pressure, and less than 8% weight loss following being immersed in phosphate-buffered saline for 16 weeks. Furthermore, the biodegradable stents delivered high rapamycin concentrations for over 4 weeks and achieved substantial reductions in intimal hyperplasia associated with elevated heme oxygenase-1 and calponin level on the denuded rabbit arteries during 6 months of follow-up. The drug-eluting cable-tie type stents developed in this study might have high potential impacts for the local drug delivery to treat various vascular diseases.

Augmentation of diabetic wound healing and enhancement of collagen content using nanofibrous glucophage-loaded collagen/PLGA scaffold membranes.

This work developed nanofibrous drug-loaded collagen/poly-D-L-lactide-glycolide (PLGA) scaffold membranes that provided the sustained release of glucophage for the wounds associated with diabetes. PLGA, glucophage, and collagen were firstly dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol and were spun into nanofibrous membranes by electrospinning. High-performance liquid chromatography assay was used to characterize the in vivo and in vitro release rates of the pharmaceuticals from the membranes. High concentrations of glucophage were released for over three weeks from the nanofibrous membranes. The nanofibrous glucophage-loaded collagen/PLGA membranes were more hydrophilic than collagen/PLGA membranes and exhibited a greater water-containing capacity. The glucophage-loaded collagen/PLGA membranes markedly promoted the healing of diabetic wounds. Moreover, the collagen content of diabetic rats using drug-eluting membranes was higher than that of the control rats, because of the down-regulation of matrix metalloproteinase 9. The experimental results herein suggest that the nanofibrous glucophage-loaded collagen/PLGA membranes had effect for increasing collagen content in treating diabetic wounds and very effective promoters of the healing of such wounds in the early stages.

Promoting Diabetic Wound Therapy Using Biodegradable rhPDGF-Loaded Nanofibrous Membranes: CONSORT-Compliant Article.

The nanofibrous biodegradable drug-loaded membranes that sustainably released recombinant human platelet-derived growth factor (rhPDGF-BB) to repair diabetic wounds were developed in this work.rhPDGF-BB and poly(lactic-co-glycolic acid) (PLGA) were mixed in hexafluoroisopropyl alcohol, followed by the electrospinning of the solutions into biodegradable membranes to equip the nanofibrous membranes. An elution technique and an enzyme-linked immunosorbent assay kit were used to determine the rhPDGF-BB release rates in vitro and in vivo from this membrane. Eighteen Sprague-Dawley streptozotocin-induced diabetic rats were randomized into 3 groups: rhPDGF-BB-loaded nanofibrous membrane group, PLGA only membrane group, and conventional gauze sponge group for the wound associated with diabetes of rat in each group.The nanofibrous biodegradable membranes released effective concentrations of rhPDGF-BB for over 21 days. The nanofibrous rhPDGF-BB-loaded PLGA membranes contained more water and were further hydrophilic than PLGA only fibers. The rhPDGF-BB-loaded PLGA membranes considerably helped the diabetic wounds repairing. Furthermore, the proliferative cells and angiogenesis of rats associated with diabetes by rhPDGF-BB-loaded nanofibrous membranes were greater than those of other groups, owing to the increased matrix metalloproteinase 9.These biodegradable rhPDGF-BB-loaded membranes were effective in treating diabetic wounds as very advanced accelerators during the initial phases of wound-healing process.

Acceleration of re-endothelialization and inhibition of neointimal formation using hybrid biodegradable nanofibrous rosuvastatin-loaded stents.

Incomplete endothelialization and neointimal hyperplasia of injured arteries can cause acute and late stent thromboses. This work develops hybrid stent/biodegradable nanofibers for the local and sustained delivery of rosuvastatin to denuded artery walls. Biodegradable nanofibers were firstly prepared by dissolving poly(D,L)-lactide-co-glycolide and rosuvastatin in 1,1,1,3,3,3-hexafluoro-2-propanol. The solution was then electrospun into nanofibrous tubes, which were mounted onto commercially available bare-metal stents. The in vitro release rates of the pharmaceuticals from the nanofibers were determined using an elution method and a high-performance liquid chromatography assay. The experimental results thus obtained suggest that the biodegradable nanofibers released high concentrations of rosuvastatin for four weeks. The effectiveness of the local delivery of rosuvastatin in reducing platelets was studied. The tissue inflammatory reaction caused by the hybrid stents that were used to treat diseased arteries was also documented. The proposed hybrid stent/biodegradable rosuvastatin-loaded nanofibers contributed substantially to the local and sustainable delivery of a high concentration of drugs to promote re-endothelialization, improve endothelial function, reduce inflammatory reaction, and inhibit neointimal formation of the injured artery. The results of this work provide insight into how patients with a high risk of stent restenosis should be treated for accelerating re-endothelialization and inhibiting neointimal hyperplasia.

Promoting endothelial recovery and reducing neointimal hyperplasia using sequential-like release of acetylsalicylic acid and paclitaxel-loaded biodegradable stents.

INTRODUCTION: This work reports on the development of a biodegradable dual-drug-eluting stent with sequential-like and sustainable drug-release of anti-platelet acetylsalicylic acid and anti-smooth muscle cell (SMC) proliferative paclitaxel. METHODS: To fabricate the biodegradable stents, poly-L-lactide strips are first cut from a solvent-casted film. They are rolled onto the surface of a metal pin to form spiral stents. The stents are then consecutively covered by acetylsalicylic acid and paclitaxel-loaded polylactide-polyglycolide nanofibers via electrospinning. RESULTS: Biodegradable stents exhibit mechanical properties that are superior to those of metallic stents. Biodegradable stents sequentially release high concentrations of acetylsalicylic acid and paclitaxel for more than 30 and 60 days, respectively. In vitro, the eluted drugs promote endothelial cell numbers on days 3 and 7, and reduce the proliferation of SMCs in weeks 2, 4, and 8. The stents markedly inhibit the adhesion of platelets on days 3, 7, and 14 relative to a non-drug-eluting stent. In vivo, the implanted stent is intact, and no stent thrombosis is observed in the stent-implanted vessels without the administration of daily oral acetylsalicylic acid. Promotion of endothelial recovery and inhibition of neointimal hyperplasia are also observed on the stented vessels. CONCLUSION: The work demonstrates the efficiency and safety of the biodegradable dual-drug-eluting stents with sequential and sustainable drug release to diseased arteries.