Perivascular delivery of losartan with surgical fibrin glue prevents neointimal hyperplasia after arterial injury.
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OBJECTIVE: Long-term success of revascularization procedures is limited by recurrent stenosis, a reduction in vascular lumen area that results from neointimal hyperplasia. Inhibitors of the renin-angiotensin system, such as losartan, have potential to prevent recurrent stenosis; however, to date, efficacy has not been demonstrated in either animal models or human beings. While we have previously reported that treatment with a satisfactory dose may be an important element in obtaining efficacy, oral delivery cannot achieve the required concentration. We therefore tested the ability of losartan to restrict neointimal hyperplasia after local delivery of an elevated dose in a fibrin glue. METHODS: The porcine saphenous artery was subjected to balloon angioplasty. Losartan (25 micromol/mL) was applied directly to the adventitial surface of the injured vessel after mixing with 1.0 mL of Tisseel. Neointimal formation was quantified after 14 days with morphometry, and immunologic staining was used to monitor expression of proteins associated with cell proliferation, migration, and phenotypic modulation. RESULTS: A statistically significant decrease of 82% (n = 5) in neointimal area was obtained with losartan, and cell proliferation, as defined by proliferating cell nuclear antigen (PCNA) expression, was inhibited by 97%. Reduced cyclin A expression in losartan-treated vessels confirmed that cell cycle progression was blocked; however, the presence of cytokeratin 8 and tenascin in the media and neointima of injured vessels, regardless of treatment, suggested that losartan does not restrict phenotypic modulation. Inhibition of MT1-MMP (MMP-14) expression by losartan indicated that this inhibitor likely suppresses cell migration as well. CONCLUSIONS: These data demonstrate that losartan can effectively prevent recurrent stenosis when delivered locally with a fibrin glue such as Tisseel. Our results also indicate that losartan may operate by interfering with the expression of proteins required for cell cycle progression and migration. CLINICAL RELEVANCE: Release of angiotensin II in response to vascular injury may promote neointimal hyperplasia, because this hormone can stimulate smooth muscle cell proliferation and migration. This study demonstrates that local application of an angiotensin receptor antagonist, losartan, to the site of injury can effectively prevent neointimal hyperplasia after balloon angioplasty. Application of losartan to the perivascular surface of the injured vessel in a surgical fibrin glue enabled delivery of a dose that exceeds the maximum attainable, via a systemic delivery route. The glue also served as a depot from which the drug was slowly released over time. Treatment with losartan may be a viable approach for controlling neointimal hyperplasia at locations (eg, grafts) that are accessible during a surgical procedure. (+info)
Paradoxical effects of elastase inhibitor guamerin on the tissue repair of two different wound models: sealed cutaneous and exposed tongue wounds.
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Innate elastase inhibitors are known to be putatively involved in the regulation of tissue inflammation by inhibiting polymorphonuclear leukocyte (PMN) derived proteinases. The aim of this study was to evaluate affects of leukocyte elastase suppression and PMN infiltration on wound healing in mouse by administering the recombinant elastase inhibitor guamerin (rEIG) in two different wound models; 1) impaired pin-punctured dorsal mucosa of anterior tongue wound, 60 mice, treated with saline containing rEIG that were fed ad libitum and 2) stable linear excisional cutaneous wound, 40 mice, covered with fibrin sealant containing rEIG. The progress of healing was analyzed by histological methods. The tongue wounds treated with rEIG became edematous around the pin-punctured tongue wound, and influx of inflammatory cells and PMN into the underlying stromal tissue were seen rapidly after wounding and peaked between 2-4 days. Whereas the control mice showed almost no wheal formation in the pin-punctured wound, a far lesser levels of PMN infiltration, and almost complete wound closure in 4 days. In the other model, the liner excisional cutaneous wound treated with fibrin sealant containing rEIG showed early wound constriction, lesser degree of inflammatory cells influx, and complete reepithelialization in 4-5 days, whereas the wound of control mice with the fibrin sealant alone showed contrary delayed reepithelialization, greater degree of inflammatory cell infiltration, and consequencial formation of greater granulation tissue at wound site. Taken together, these data suggest paradoxical effects of rEIG on the wound healing where in the wound exposed to infiltrating milieu of microorganisms in the oral cavity, the rEIG aggravates the wound healing by interfering with other innate defensive factors and extended greater flux of PMNs to inflamed wound site, while in the wound enclosed by fibrin, the rEIG accelerated wound healing by inhibiting the inflammation-generated proteases and the acute inflammatory reaction. (+info)
Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium.
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OBJECTIVES: In this study, we determined whether fibrin glue improves cell transplant retention and survival, reduces infarct expansion, and induces neovasculature formation. BACKGROUND: Current efforts in restoring the myocardium after myocardial infarction (MI) include the delivery of viable cells to replace necrotic cardiomyocytes. Cellular transplantation techniques are, however, limited by transplanted cell retention and survival within the ischemic tissue. METHODS: The left coronary artery of rats was occluded for 17 min followed by reperfusion. One week later, bovine serum albumin (BSA), fibrin glue, skeletal myoblasts in BSA, or skeletal myoblasts in fibrin glue were injected into the infarcted area of the left ventricle. The animals were euthanized five weeks after injection, and their hearts were excised, fresh frozen, and sectioned for histology and immunohistochemistry. RESULTS: After five weeks, the mean area covered by skeletal myoblasts in fibrin glue was significantly greater than the area covered by myoblasts injected in BSA. Myoblasts within the infarct were often concentrated around arterioles. The infarct scar size and myoblasts in the fibrin group were significantly smaller than those in the control and BSA groups. Fibrin glue also significantly increased the arteriole density in the infarct scar as compared with the control group. CONCLUSIONS: This study indicates that fibrin glue increases cell transplant survival, decreases infarct size, and increases blood flow to ischemic myocardium. Therefore, fibrin glue may have potential as a biomaterial scaffold to improve cellular cardiomyoplasty treat and MIs. (+info)
Fixation of osteochondral fractures in rabbit knees. A comparison of Kirschner wires, fibrin sealant, and polydioxanone pins.
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We compared fibrin sealant, polydioxanone (PDS) pins and Kirschner wires in the fixation of osteochondral fractures in rabbit knees. Standardised osteochondral fractures of the right medial femoral condyle were made in 56 adult New Zealand white rabbits. There were equal groups of control knees, and those which had Kirschner-wire, fibrin-sealant or PDS-pin fixation. No external immobilisation was used. One animal from each group was killed at two, three and four weeks. The remaining rabbits were killed at six weeks. A fracture which healed with less than 1 mm of displacement was considered a success. There was successful healing in 29% of the control group, in all of the Kirschner-wire group, in 50% of the fibrin-sealant group, and in 86% of the PDS-pin group. The use of PDS pins appears to be a reliable alternative to the use of metal in the fixation of osteochondral fractures in rabbits. (+info)
MRSA aortic valve endocarditis treated by pericardium-lined Dacron patch and vancomycin-containing fibrin glue.
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A 40-year-old man was admitted with a diagnosis of MRSA aortic valve endocarditis. He was treated conservatively with clindamycin and vancomycin for three days, but embolism occurred into the brain and the right lower limb, and urgent aortic valve replacement was performed. Resecting an aortic annular abscess resulted in a huge defect of the root. The defect was reconstructed with a combined patch: a Dacron graft lined with pericardium using vancomycin-containing fibrin glue. Although complete healing of the infected leg wound was slow, no prosthetic valve endocarditis has been detected in the 11 months since operation. (+info)
Surgical management of cerebrospinal fluid rhinorrhea under endoscopic control.
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The surgical management of cerebrospinal fluid (CSF) rhinorrhea has changed after the introduction of functional endoscopic sinus surgery.The following three cases illustrate the repair of CSF leaks with the use of rigid endoscope. Two patients had the diagnosis and the site confirmed after intrathecal fluoresceine saline injection. The obliteration of the CSF was achieved with fat free, mucoperichondrial or mucoperiostal free grafts taken from middle or inferior turbinate and kept in place by fibrin glue. Primary closure was achieved in all patients. The repair of the CSF rhinorrhea by endonasal endoscopic surgery is safe, effective and is a valid alternative to the cranial approach. (+info)
A review of bioceramics and fibrin sealant.
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This review focuses on bone substitute composites made by mixing ceramic biomaterials with fibrin sealants. Different biomaterials such as coral, bone-derived materials, bioactive glass ceramics, and synthetic calcium phosphate have been mixed with fibrin sealant, resulting in a combination of the biological properties of the two components. This type of association has not produced identical results in all studies. In the past for some, the addition of fibrin sealant to the biomaterial failed to produce any significant, positive effect on osteointegration, whereas others found a positive impact on bone colonization. Despite the negative biological effects reported previously, bioceramic-fibrin composites have been widely used in various types of bone surgery because they are easy to manipulate. In particular, the intra-operative preparation of these composites makes it possible to add bone growth factors or autologous osteoprogenitor cells prior to bone reconstruction. The bone growth factors and autologous osteoprogenitor cells associated with the bioceramic-fibrin composites should provide surgeons with tissue engineered grafts with enhanced osteointegrative properties. This review discusses both the advantages and disadvantages, as well as the future perspectives, of using bioceramic-fibrin composites in various clinical indications. (+info)
Tissue adhesives for a sutureless fadenoperation: an experimental study in a rabbit model.
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PURPOSE: To use tissue adhesives for a sutureless Fadenoperation to eliminate perioperative risks related to the sutures. METHODS: In an in vivo procedure, 120 superior recti muscles in New Zealand White rabbits were subjected to the posterior fixation procedure, at a distance of 6 mm from the insertion point of the muscle. They were divided into four groups of 30 muscles, according to the material used to perform a myopexy: group 1 (control): nonabsorbable 5-0 polyester sutures; group 2: n-butyl-2-cyanoacrylate adhesive; group 3: fibrin glue; group 4: gelatin-resorcin-formaldehyde-glutaraldehyde (GRFG) adhesive. The animals were examined at 1, 7, 14, and 21 days after surgery. Afterward, they were killed, and their eyes were enucleated to measure the distance between the myopexy and the anatomic insertion point and to assure the strength of the bond with a dynamometer. Finally, a histologic examination was performed. RESULTS: Almost all eyes were clear after the third week, although group 4 presented the most intense inflammatory reaction. In histologic examination, groups 1 and 2 showed a chronic inflammatory reaction of the foreign-body type, with similar intensity. Fibrin glue induced minimal inflammation, but GRFG adhesive produced a pronounced reaction. Concerning the distance of the myopexy, groups 1 and 2 presented measures close to the expected distance of 6 mm, whereas groups 3 and 4 showed a greater variability. All groups performed well in the strength test, with no statistically significant differences among them. CONCLUSIONS: n-Butyl-2-cyanoacrylate adhesive performed best in the sutureless Fadenoperation, characterized by precision in the expected distance of myopexy, sufficient resistance to separation, and acceptable inflammatory reaction. (+info)