Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Objetivo: Medir a pulsatilidade da parede do aneurisma de aorta humano antes e depois de sua correção endoluminal. Método: Cinco aneurismas foram submetidos à perfusão pulsátil antes e depois do implante de uma endoprótese. Resultado: o nível da coluna de água oscilou durante a pulsação com variações de 17, 16, 13, 7 e 25 cm antes da colocação da endoprótese. Depois da prótese, a oscilação diminuiu em todos os casos para 13, 12, 9, 3,5 e 23 cm, respectivamente. Conclusão: A pulsação da endoprótese é transmitida à parede do aneurisma / Objective: To measure the pulsatility of human aortic aneurysms before and after exclusion with endograft. Method: Five aneurysms were submitted to pulsatile perfusion before and after implantation of a bifurcated endograft. Result: The level of the water column oscillated during pulsation, in each case, with an amplitude of 17, 16, 13, 7 and 25 cm before the endograft insertion. After that, the amplitudes dropped to, respectively 13, 12, 9, 3.5 and 23 cm.Conclusion: Pulsation of an endograft is transmitted to the aneurysm wall even in the absence of endoleak

Submitted by Fabíola Silva (fabiola.silva@famerp.br) on 2017-05-25T19:30:55Z No. of bitstreams: 1 antoniocarlosbrandi_tese.pdf: 1540715 bytes, checksum: 85572fb595b07fb61d81ed453db08401 (MD5) / Made available in DSpace on 2017-05-25T19:30:55Z (GMT). No. of bitstreams: 1 antoniocarlosbrandi_tese.pdf: 1540715 bytes, checksum: 85572fb595b07fb61d81ed453db08401 (MD5) Previous issue date: 2015-05-20 / Introduction: Thoracic aortic diseases, including dissections, aneurysms, pseudoaneurysms among other, are serious conditions that bring serious risks of morbidity and mortality. Its incidence is low, but has been growing gradually due to the increase in life expectancy of the population, that in most cases, is associated with hypertension, smoking and diabetes mellitus. Advances in diagnostic techniques have also contributed to the identification of an increasing number of cases. The development of minimally invasive endovascular procedures has been used successfully in the treatment of these diseases, including patients with no indication for conventional surgical treatment. Objective: Evaluate the long-term results of endovascular treatment of patients with diseases of the thoracic aorta underwent implantation of self-expandable stent-grafts. Methods: This prospective study evaluated 112 patients who underwent percutaneous implantation of endoprosthesis of the thoracic aorta, from October 1998 to August 2013. Self-expandable endoprosthesis stent-graft Braile Biomédica ®, made of stainless steel and nitinol were employed. The occurrence of intraoperative and postoperative primary success, endoleaks, mortality, late evolution of the endoprosthesis and survival were evaluated in long term follow-up. Results: The mean time of the procedures was 72.66 ± 43.36 minutes (range 30-240 minutes). A total of 150 self-expandable stents were implanted in 112 patients, 61 (40.66%) of stainless steel and 89 (59.33%) of nitinol. The diameter and length of the stents of stainless steel and nitinol ranged from 24-45 mm (median 33) and 70-130 mm (median 90) 22-46 mm (median 35) and between 40 and 230 mm (median 110) respectively. The number of stents implanted per patient ranged from 1 to 4 (median 1). Primary success was observed in 100 (82.14%) of 112 patients treated. Immediate mortality occurred in seven (6.25%) patients, five (4.46%) from cardiovascular causes and two (1.78%) for non-cardiovascular causes. Late mortality occurred in 31 (27.68%) patients, 10 (8.93%) from cardiovascular causes, 12 (10.71%) for non-cardiovascular causes, two (1.78%) from natural causes-seven (6.25%) with no diagnosis. There hospital type I endoleaks occurred in four patients (3.57%), type II in five (4.46%) and three type IV (2.68%). Late endoleaks type I occurred in five (4.46%) patients and type IV in three (2.68%). Twenty-two patients (19.64%) had clinical complications in the immediate postoperative period, including nine (8.03%) pulmonary complications, four (3.57%) neurological abnormalities, three (2.67%) acute renal failure, two (1.78%) infections in the surgical incision, two (1.78%) with progression to post-implantation syndrome and one (0.89%) with laceration of the arterial access. Follow-up time ranged from 1 to 179 months (median 46). The acturial survival curve was 79,3% (IC95% 67,0-91,7) at 132 months free of death from cardiovascular causes. The logistic regression analysis showed that renal failure was the only risk factor that showed a statistically significant difference. Conclusions: The low levels of intra and postoperative complications demonstrate that the treatment is safe and effective. The high rate of survival after 132 months of follow-up for these critically ill patients show the benefits of endovascular technique to treatment of thoracic aorta diseases. / Introdução: Doenças da aorta torácica, incluindo as dissecções, aneurismas, pseudoaneurismas entre outras, são condições graves que trazem sérios riscos de morbimortalidade. Sua incidência é baixa, porém, vem crescendo gradativamente em virtude do aumento da expectativa de vida da população que, na maioria dos casos, está associada à hipertensão arterial, tabagismo e diabetes. Os avanços nas técnicas diagnósticas também têm contribuído para a identificação de um número cada vez maior de casos. O desenvolvimento de procedimentos endovasculares minimamente invasivos vem sendo utilizado com sucesso no tratamento destas doenças, inclusive em pacientes sem indicação para tratamento cirúrgico convencional. Objetivo: Avaliar os resultados em longo prazo do tratamento endovascular de pacientes portadores de doenças da aorta torácica submetidos ao implante de endopróteses autoexpansíveis stent-grafts. Casuística e Métodos: Estudo prospectivo que avaliou 112 pacientes submetidos ao implante percutâneo de endoprótese na aorta torácica, no período de outubro de 1998 a agosto de 2013. Foram empregadas endopróteses autoexpansíveis stent-grafts da Braile Biomédica®, confeccionadas em aço inox e nitinol. Foram avaliadas a ocorrência de complicações intra e pós-operatórias, sucesso primário, endoleak, mortalidade, evolução tardia da endoprótese e a sobrevivência em seguimento de longo prazo. Resultados. O tempo médio dos procedimentos foi de 72,66±43,36 minutos (variação 30-240 minutos). Foram implantadas um total de 150 endopróteses autoexpansíveis em 112 pacientes, sendo 61 (40,66%) de aço inox e 89 (59,33%) de nitinol. O diâmetro e comprimento dos stents de aço inox e de nitinol variaram de 24-45 mm (mediana 33) e 70-130 mm (mediana 90), 22-46 mm (mediana 35) e 40 a 230 mm (mediana 110), respectivamente. O número de endopróteses implantadas por paciente variou de 1 a 4 (mediana 1). Sucesso primário foi observado em 100 (82,14%) dos 112 pacientes tratados. A mortalidade hospitalar ocorreu em sete (6,25%) pacientes, cinco (4,46%) por causas cardiovasculares e dois (1,78%) por causas não cardiovasculares. A mortalidade tardia ocorreu em 31 (27,68%) pacientes, 10 (8,93%) por causas cardiovasculares, 12 (10,71%) por causas não cardiovasculares, dois (1,78%) por causas naturais e sete (6,25%) sem diagnóstico. No período hospitalar, ocorreu endoleak do tipo I em quatro pacientes (3,57%), tipo II em cinco (4,46%) e tipo IV em três (2,68%). Endoleak tardio do tipo I ocorreu em cinco (4,46%) pacientes e do tipo IV em três (2,68%). Vinte e dois pacientes (19,64%) apresentaram complicações clínicas no pós-operatório imediato, incluindo nove (8,03%) complicações pulmonares, quatro (3,57%) alterações neurológicas, três (2,67%) pacientes com insuficiência renal aguda, duas (1,78%) incisões cirúrgicas com infecção, duas (1,78%) síndromes pós-implante e uma (0,89%) laceração do acesso arterial. O tempo de seguimento variou de 1 a 179 meses (mediana 46). A curva atuarial de sobrevivência foi de 79,3% (IC95% 67,0-91,7) aos 132 meses livre de mortalidade por causas cardiovasculares. A análise de regressão logística mostrou que a insuficiência renal foi o único fator de risco para mortalidade que apresentou diferença estatisticamente significante. Conclusões. Os baixos índices de complicações intra e pós-operatórias demonstram que o tratamento é seguro e eficaz. O alto índice de sobrevivência após 132 meses de seguimento para estes pacientes graves mostram os benefícios da técnica endovascular no tratamento das doenças da aorta torácica.

Atherosclerosis is an inflammatory disease which develops focally in regions of the vasculature where there is dysfunction of endothelial cells modulated in part by shear stress from flowing blood. To address the clinical crisis of atherosclerosis, tissue engineering has focused on development of a living blood vessel substitute for use as a vascular graft in bypass surgery. Despite substantial progress in understanding the biological basis and developing clinical treatments for cardiovascular disease, critical challenges remain. As a novel strategy to improve understanding of basic human vascular biology and develop superior tissue engineered grafts, this dissertation combines the scientific and clinical approaches by using a tissue engineered blood vessel as a more physiologic in vitro model to study endothelial cell biology. Through the use of transcriptional profiling, results demonstrate significant changes in endothelial cell gene expression using the tissue engineered blood vessel model. Furthermore, the presence of a more physiologic substrate alters the cellular response to shear stress which is a critical mediator of vascular pathology. A case study of endothelial cell function in this system focuses on cell-cell communication through gap junctions. Endothelial cell connexins which form gap junctions are shown to be differentially regulated by substrate and shear stress. Moreover, gap junction communication between endothelial cells is modulated by the mechanical environment. Studies using RNA interference to knockdown expression of individual connexin isotypes demonstrate integrated regulation of connexins yet unique roles in endothelial cell function. Collectively, results exemplify the sensitivity of endothelial cell phenotype to substrate and shear stress and underline the importance of using more physiologic models in the study of basic cell biology.

Abdominal aortic aneurysms are a leading cause of death in the U.S. where 14,000 people die from aneurysm rupture and 178,000 are diagnosed each year. A novel alternative treatment for abdominal aortic aneurysms has been proposed, where a biodegradable polymer scaffold is photopolymerized in situ around the exterior of the aneurysm. This scaffold will mechanically constrain the aneurysm from further expansion, and will deliver a drug, doxycycline, to treat the underlying biological cause of the disease. In order for device development, a suitable polymer must be designed with appropriate mechanical properties, degradation rate, polymerization, and elution rate. Poly(β-amino ester) networks have been proposed as the material of choice; however, many of their structure-property relationships have yet to be determined. Therefore, the overall goal of this work is to determine the structure-property relationships of the poly(β-amino ester) networks in order to advance the design of the treatment, and has been divided into three objectives: (1) understand the structure-property relationships of poly(β-amino ester) networks, specifically the polymerization, degradation rate, and thermo-mechanical properties, (2) determine the impact of doxycycline incorporation on degradation rate and mechanical properties, (3) evaluate the effect of simulated physiological conditions on degradation rate and mechanical properties. In the initial chapters, the fundamental structure-property relationships are established between reactant chemical structure, step-growth polymerization, photopolymerization, thermo-mechanical properties, and degradation rate using a systematic approach of two homologous series of reactants. Further tailoring of degradation rate, water content, and modulus in vitro was performed by using a copolymer network. Doxycycline inhibited photopolymerization due to overlapping absorbance spectra with the photoinitiator, but full network formation occurred by increasing the photoinitiator concentration. Networks displayed varying controlled release rates, and the underlying release mechanism was determined for each network using established methods. In order to increase mechanical properties, a co-monomer, methyl methacrylate, was added to the network to increase the glass transition temperature, toughness, and deformation capacity. These co-networks displayed temporal-control of mechanical properties in simulated physiological conditions, since degradation caused a shift in the glass transition temperature, which changed the mechanical behavior of the network. The temporal-control of mechanical properties was further investigated under degradation conditions in vitro and in vivo. Due to the mechanically active loading environment in vivo, networks displayed a decrease in toughness, yet maintained mechanical properties similar to native biological tissues. These networks establish a multifunctional biomaterials platform with materials that can be easily synthesized, photopolymerized into various geometries, and sustain mechanical properties while undergoing degradation and therapeutic agent release.

The development of small diameter tissue engineered blood vessels (TEBVs) with low thrombogenicity, low immunogenicity, suitable mechanical properties, and a capacity to remodel to their environment could significantly advance the treatment of coronary and peripheral artery disease. Despite significant advances in the field of tissue engineering, autologous vessels are still primarily utilized as grafts during bypass surgeries. However, undamaged autologous tissue may not always be available due to disease or prior surgery. TEBVs lack long-term efficacy due to a variety of types of failures including aneurysmal dilations, thrombosis, and rupture; the mechanisms of these failures are not well understood. In vitro mechanical testing may help the understanding of these failure mechanisms. The typical mechanical tests lack standardized methodologies; thus, results vary widely. The overall goal of this study is to develop novel experimental and mathematical models to study the mechanical properties and failure mechanisms of TEBVs. Our results suggest that burst pressure tests, the current standard, are not sufficient to assess a TEBVs’ suitability as a coronary substitute; creep and/or cyclic loading tests are also required. Results from this model can help identify the most insightful experiments and quantities to be measured – ultimately reducing the overall number of experimental iterations. Improving the testing and characterization of TEBVs is critically important in decreasing the time necessary to validate the mechanical and functional responses of TEBVs over time, thus quickly moving TEBVs from the benchtop to the patient.

Compliance mismatch is a significant hurdle to long-term patency in small-diameter arterial bypass grafts. Vascular tissue engineering has the potential to produce compliant, non-thrombogenic small-diameter grafts. However, current engineered grafts are relatively non-compliant, resulting in intimal hyperplasia and graft occlusion when subjected to arterial pressures. This research investigates the mechanical and biological properties of engineered constructs based on a biodegradable synthetic elastomer, poly(glycerol sebacate) (PGS). Several methods for fabricating porous PGS scaffolds in a tubular geometry were developed and compared. Adult baboon vascular cells were cultured in the scaffolds under various in vitro experimental conditions, including variations in initial cell seeding density, the type of scaffold used for culture, culture time, scaffold material, and hydrostatic pressure, and properties of the resultant constructs were compared. Scaffold fabrication using heat-shrinkable mandrels and glass tubes coated with hyaluronic acid significantly decreased tolerances of wall thickness and mechanical properties, improved handling, and decreased culture time required to reach luminal cellular confluence compared to scaffolds made with other fabrication techniques. Altering scaffold material from PGS to poly(lactide-co-glycolide) (PLGA), a benchmark biomaterial, did not affect scaffold yield, porosity, or luminal cellular confluence. Extracellular matrix (ECM) deposition increased with SMC-only culture time, and ECM deposition and remodeling during culture influenced construct compliance. Compared to PLGA scaffolds, PGS scaffolds promoted elastin crosslinking by SMCs and elastic tissue properties but attenuated collagen deposition. Hydrostatic pressure promoted ECM synthesis and deposition by SMCs and decreased construct compliance. Collagen and crosslinked elastin content in constructs correlated positively with construct burst pressure, and a negative correlation dependent on scaffold type was found between collagen content and construct compliance at low pressures. The systematic investigation of culture conditions in this research provides insights into the control of engineered blood vessel properties. The central hypothesis of this work, that grafts engineered from PGS scaffolds and adult vascular cells under biomimetic in vitro culture conditions can possess compliance comparable to autologous vessels, is true at pressures below 60 mmHg and demonstrates potential for PGS-based vascular tissue engineering. Overall, this work provides tools for engineering tubular soft tissues based on porous PGS scaffolds.

Objetivo: Medir a pulsatilidade da parede do aneurisma de aorta humano antes e depois de sua correção endoluminal. Método: Cinco aneurismas foram submetidos à perfusão pulsátil antes e depois do implante de uma endoprótese. Resultado: o nível da coluna de água oscilou durante a pulsação com variações de 17, 16, 13, 7 e 25 cm antes da colocação da endoprótese. Depois da prótese, a oscilação diminuiu em todos os casos para 13, 12, 9, 3,5 e 23 cm, respectivamente. Conclusão: A pulsação da endoprótese é transmitida à parede do aneurisma / Objective: To measure the pulsatility of human aortic aneurysms before and after exclusion with endograft. Method: Five aneurysms were submitted to pulsatile perfusion before and after implantation of a bifurcated endograft. Result: The level of the water column oscillated during pulsation, in each case, with an amplitude of 17, 16, 13, 7 and 25 cm before the endograft insertion. After that, the amplitudes dropped to, respectively 13, 12, 9, 3.5 and 23 cm.Conclusion: Pulsation of an endograft is transmitted to the aneurysm wall even in the absence of endoleak

Abstract Endovascular aneurysm repair (EVAR) is a minimally invasive alternative to open surgery to exclude an abdominal aortic aneurysm from the circulation to avert a rupture. The aim of this thesis was to evaluate the early and mid-term results of EVAR using the Zenith® stent-graft (Cook Inc, Bloomington, IN, USA) in asymptomatic and symptomatic abdominal aortic aneurysm (AAA) patients in three Finnish university hospitals. Furthermore, the aim was to study whether preoperative embolization of the inferior mesenteric artery (IMA) before EVAR decreases the incidence of a type II endoleak or has an effect on the aneurysm sac shrinkage. Finally, the results after secondary interventions for a type II endoleak were evaluated. Two hundred six patients underwent elective endovascular repair of an intact AAA. The use of the Zenith® stent-graft was associated with good early and mid-term results. The thirty-day mortality rate (2.9%) was in accordance with other EVAR studies. Only one late aneurysm-related death occurred in this series, whilst no patients died of a late aneurysm rupture. No stent-graft migrations or fractures were observed. Endoleak, defined as persistent blood flow outside the graft and within the aneurysm sac, remains a long-term problem with EVAR. The overall endoleak incidence was 34.6%. A type II endoleak (retrograde perfusion via aortic side branches) occurred in 52 patients (25.4%). EVAR was performed for 14 patients with a symptomatic, unruptured AAA. The median delay from admission to intervention was 4 days. EVAR of a symptomatic, unruptured AAA was associated with a favourable outcome even in patients with a very high operative risk. There were no perioperative deaths. Altogether forty patients treated at Kuopio University Hospital had a patent IMA on preoperative computed tomography (CT) and were treated successfully with coil embolization before EVAR. Thirty-nine patients who underwent EVAR at Oulu University Hospital without preoperative embolization of a patent IMA served as a control group. Preoperative coil embolization of the IMA significantly reduced the incidence of type II endoleaks after EVAR, but the present study failed to show any influence on late postoperative aneurysm sac shrinkage. Overall, 14 patients underwent a secondary intervention to repair the type II endoleak. Ten patients had transarterial embolization and four patients had translumbar embolization. The results were unsatisfactory; clinical success after the first secondary intervention was achieved in only two patients in the transarterial embolization group and three patients in the translumbar embolization group. These results seem to favour direct translumbar embolization rather than transarterial embolization. In conclusion, EVAR with the Zenith® stent-graft is effective in excluding AAAs from the circulation and is associated with good mid-term results.

The purpose of this study was to evaluate the effectiveness of aspirin (ASA) and porcine endothelial cell seeding in improving the patency rate of vena cava grafts. Thirty-nine dogs underwent infrarenal vena cava replacement by 10 cm lengths of 8 mm I.D. ringed polytetrafluoroethylene grafts. Thirty-one grafts were seeded with 1-1.5 x 10(6) porcine aortic endothelial cells while eight were not (GIII). Of the seeded group, 16 animals received no ASA (GI), while 15 others (GII) were given ASA (325 mg) daily starting two days preoperatively and continuing until sacrifice. Venograms were performed on the fourth postoperative day. Grafts were harvested 32 days after insertion and evaluated for patency rate and endothelialized surfaces. The 32-day patency rate was significantly higher for GII than for GI and III animals (67% vs. 13 and 25% respectively). Endothelialized surface was higher in GII than Gi and III (67% vs. 16% and 18% respectively). We conclude that endothelial cell seeding alone does not prevent graft closure and that a combination of ASA and cell seeding significantly increases the patency rate of vena cava grafts.