Enhanced efficacy of sirolimus-eluting bioabsorbable magnesium alloy stents in the prevention of restenosis.

PURPOSE: To determine the efficacy of sirolimus-eluting bioabsorbable magnesium alloy stents (SEBMAS) in restenosis prevention. METHODS: A balloon-expandable bioabsorbable magnesium alloy stent (BMAS) was created and coated with biodegradable poly(lactic acid-co-trimethylene carbonate) that contained the antiproliferative drug sirolimus (140 ± 40 µg/cm²). Both the uncoated BMAS and the coated SEBMAS were deployed 2 cm apart in balloon-injured infrarenal abdominal aortas of 20 New Zealand white rabbits. The stented aortic segments were removed at 30, 60, 90, and 120 days (5 rabbits per interval) after implantation. The average stent strut sectional area of each group was measured to evaluate the degree of magnesium corrosion and to forecast the biodegradation time profile of the magnesium stent. Histology and histopathology of the sectioned stented aortic segments were performed to evaluate neointima formation, endothelialization, and inflammation. RESULTS: The SEBMAS degraded gradually after being implanted into the rabbit aorta, and total biocorrosion occurred after ~120 days. In all groups, the lumen area was significantly greater, but the neointimal area was significantly smaller in SEBMAS segments compared with the uncoated BMAS segments (p < 0.05) at all time points. There was no significant difference in the injury or inflammation scores between the groups. Endothelialization was delayed at 30 days in the SEBMAS segments vs. the uncoated BMAS segments. CONCLUSION: SEBMAS further reduces intimal hyperplasia and improves the lumen area when compared to uncoated BMAS; however, it delays vascular healing and endothelialization.

Gene transduction into aortic wall using plasmid-loaded cationized gelatin hydrogel-coated polyester stent graft.

OBJECTIVE: Stent grafts are increasingly recognized as useful devices for endovascular repair of aortic aneurysms and other vascular diseases. Stent graft-mediated gene delivery into the vascular wall is expected to improve their therapeutic effects. This study evaluated the efficacy of genetically engineered cationized gelatin (CG) hydrogel-coated partially-covered polyester stent grafts that facilitate delivery of an expression plasmid DNA in rabbit aortic wall. METHODS: Partially covered polyester stent grafts coated with CG hydrogel impregnated with 10.0 mg/mL of beta-galactosidase (LacZ)-expression plasmid vector (pCAGGS-LacZ) or empty vector (pCAGGS) solutions were implanted via the femoral artery in rabbit balloon-injured aortas. The aortic segments were removed at 1, 3, or 7 days (4 rabbits/each group) after implantation and evaluated for the transgene (LacZ) delivery and expression by real-time reverse transcriptase polymerase chain reaction (RT-PCR) and X-gal (5-bromo-4-chloro-3-indolyl-beta-D-galactoside) staining. Partially-covered polyester stent grafts coated with CG hydrogel impregnated with various amounts (0.1 mg/mL, 1.0 mg/mL, and 10.0 mg/mL) of pCAGGS-LacZ or pCAGGS were also implanted in rabbits' balloon-injured aortas (4 rabbits/each group) to evaluate transgene delivery and expression in the aortic wall 3 days after implantation. The difference of transgene efficiency among each group was compared using one-way analysis of variance (ANOVA) and Newman-Keuls' test according to the result of quantitative RT-PCR. RESULTS: In all animals, LacZ gene transduction into the aortic wall was detected at the implantation site of pCAGGS-LacZ-loaded, but not pCAGGS-loaded, stent grafts. LacZ expression was not detected in aortic segments immediately proximal or distal to the implanted pCAGGS-LacZ-loaded stent graft or remote organs including the brain, heart, liver, and kidney by either RT-PCR or X-gal staining. The X-gal staining-positive cells were observed at or near the luminal surface in the aortic segments only in contact with the stent graft and the ingrowth tissues within stent grafts. Immunohistochemical studies suggested that the LacZ-positive cells were mainly the neointimal alpha-smooth-muscle actin-positive cells and macrophages. The extent of the transgene expression was dependent on the quantity of the plasmid DNA loaded onto the stent graft (10.0 mg/mL plasmid vs 1.0 mg/mL plasmid, P < .01 and 10.0 mg/mL plasmid vs 0.1 mg/mL plasmid, P < .05). LacZ mRNA expression was maximal at day 1 and declined at day 7 (P < .05) but was still detectable. CONCLUSION: Plasmid-loaded CG hydrogel-coated stent graft is a promising vehicle for local transgene delivery to the aortic wall and offers the possibility of transduction of therapeutic genes into the vascular wall.

In vitro study of stimulation effect on endothelialization by a copper bearing cobalt alloy.

Endothelialization is an important process after stenting in coronary artery. Recovery of the injured site timely can reduce the neointima formation and platelet absorbance, leading to a lower risk of in-stent restenosis. Copper is known to be critical in vascular construction. Thus a combination of copper with stent materials is a meaningful attempt. A copper bearing L605-Cu cobalt alloy was prepared and its effect on human umbilical vein endothelial cells (HUVECs) was evaluated in vitro in this study. It was found that HUVECs attached and stretched better on the surface of L605-Cu compared with L605, and the apoptosis of cells was decreased simultaneously. The migration and tube formation of HUVECs were also enhanced by the extract of L605-Cu. Furthermore, L605-Cu increased the mRNA expression of VEGF in HUVECs significantly. However it had no effect on the secretion of NO or mRNA expression of eNOS. The result of blood clotting test indicated that L605-Cu had better blood compatibility. These results above have demonstrated that the L605-Cu alloy is promising to be a new stent material with function of accelerating endothelialization. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 561-569, 2018.

Biocompatible and biodegradable zeolitic imidazolate framework/polydopamine nanocarriers for dual stimulus triggered tumor thermo-chemotherapy.

Zeolitic imidazolate frameworks (ZIFs) have attracted great interest as pH-sensitive drug carrier because of high drug loading and intrinsic biodegradability. In this work, a biocompatible NIR and pH-responsive drug delivery nanoplatform based on ZIFs (PDA-PCM@ZIF-8/DOX) is synthesized for in vivo cancer therapy. The biocompatibility of ZIFs is greatly improved by polydopamine (PDA) modifying and proved by cytotoxicity and in vivo acute toxicity evaluation. The degradability is also regulated in an appropriate rate. Due to mild reaction condition of ZIFs, the synthesis and drug loading is achieved in one pot with high loading (37.86%) and encapsulation rate (78.76%). Meanwhile, PDA acts as a photothermal transfer agent to trigger thermal response switch of phase change materials for NIR controlled drug release. Under the dual stimulus of NIR and acid environment, the drug release is as high as 78%, while only 21% is released without stimulus, showing a remarkable effect of control release. In vivo anti-tumor experiments demonstrate the high tumor inhibition rate of photothermal-chemotherapy group with a significant synergistic effect. The biocompatible and biodegradable drug delivery platform based on ZIFs has shown great promise for future clinic cancer therapy.

Evaluation of promoting effect of a novel Cu-bearing metal stent on endothelialization process from in vitro and in vivo studies.

Drug eluting stents (DES) have been extensively applied nowadays and reduce the incidence of in-stent restenosis (ISR) greatly as compared with bare metal stents (BMS). However, the development of DES is hindered by the risk of late stent thrombosis (LST) due to delayed re-endothelialization, while endothelialization is an important process related to ISR and LST after implantation. 316L is a traditional stent material without bioactivity and have a high risk of ISR. Cu is recognized for angiogenesis stimulation in these years. Hence a copper bearing 316L stainless steel (316L-Cu) was prepared and evaluated about its effect on endothelialization in this paper. Compared with traditional 316L, it was proved that 316L-Cu increased the proliferation of co-cultured human umbilical vein endothelial cells (HUVECs) at first day. Moreover, HUVECs stretched better on the surface of 316L-Cu. It also improved the expression of angiogenesis related genes and tube formation ability in vitro. 316L-Cu-BMS, DES and 316L-BMS were implanted in swine to evaluate the re-endothelialization ability in vivo. And 316L-Cu-BMS showed the best effect on endothelialization with good biosafety. Consequently, 316L-Cu is a kind of promising BMS material for coronary field.

Partially covered stent-graft implantation in rabbit aorta: a new model to investigate bioactive stent-grafts in small animals.

PURPOSE: To present a new endovascular technique for placing handmade partially covered stent-grafts in rabbit aortas that is promising for experimental study of direct gene delivery to the aortic wall. METHODS: A 7-mm-diameter Z-stent made from the inner core of a guidewire was covered with a 7-mm-diameter, 10-mm-long polyester fabric tube (2268 mL porosity). To decrease stent profile and make delivery possible through a 6-F introducer, one third of the fabric was cut away to form a partially covered polyester stent-graft. Two stent-grafts were delivered sequentially into the descending thoracic aorta of 12 male Japanese White rabbits; a third device was positioned in each aorta so that the orifices of the celiac trunk and superior mesenteric artery were not occluded. RESULTS: The implantation was successful in 10 animals. One rabbit died during the procedure due to sheath laceration of the infrarenal abdominal aorta. Another animal died within 2 days after the procedure owing to occlusion of the celiac trunk by graft fabric. At 2 weeks, the stent-grafts in the 10 surviving rabbits remained patent, and there was no migration. Gross examination of the lumens showed that both the metal stent and the polyester graft material were completely covered with thin transparent tissue, without massive thrombosis. Histological staining revealed incomplete neointima formation between the stent-graft and the aorta. Incomplete linear endothelial cells on the luminal side of the tissue ingrowth into the stent-graft were also observed. Foreign body giant cells and macrophages represented inflammatory reactions related to the graft material. CONCLUSION: Partially covered stent-grafts can be safely placed in relatively small animals and potentially used in research.

Hydrogel-mediated release of basic fibroblast growth factor from a stent-graft accelerates biological fixation with the aortic wall in a porcine model.

PURPOSE: To evaluate the local reaction of the aortic wall induced by basic fibroblast growth factor (bFGF) released from a gelatin hydrogel coated on the outer surface of a stent-graft for the purpose of biological fixation. METHODS: A total of 18 nitinol-based, polyester-covered stent-grafts were implanted in 6 porcine aortas for 1 month. The implanted stent-grafts were divided into 3 groups: the control group (uncoated), the hydrogel group (coated with hydrogel containing water), and the bFGF group (coated with hydrogel containing bFGF). After stent-graft implantation, the results of intravascular ultrasound (IVUS) and qualitative and quantitative microscopic examinations were compared among the groups. RESULTS: In the bFGF group, a thin white lamellar tissue was observed on IVUS images. Significantly more new intimal tissue formation was observed in all the bFGF group animals than in the other 2 groups, and alpha smooth muscle (SM) actin-positive cells (alphaSMCs) were detected in this new tissue. The alphaSMCs within the fabric of tightly woven grafts were significantly more abundant in the bFGF group than in the other groups. CONCLUSION: The local controlled release of bFGF from the stent-graft significantly accelerated the proliferation of new intimal tissue between the aorta and the stent-graft and within the graft materials. These findings suggest that a graft can be fixed biologically to the aortic wall, which may contribute to the shrinkage of aneurysms following stent-grafting.