Enhanced detection of thromboemboli with the use of targeted microbubbles.

BACKGROUND AND PURPOSE: Targeted ultrasound contrast agents have recently been developed to adhere selectively to specific pathogenic materials such as plaque or thrombus. Administration of such microbubbles has potential to aid transcranial Doppler ultrasound (TCD) detection of emboli and to act as markers for distinguishing one embolic material from another. The purpose of this study was to investigate whether TCD detection of circulating thrombus emboli would be enhanced by the addition of targeted microbubbles. METHODS: Binding of microbubbles to the surface of the thrombus was confirmed by scanning electron microscopy. Targeted and control bubbles were then introduced to thrombus and tissue-mimicking material circulated under pulsatile-flow conditions in an in vitro flow rig. Embolic signal intensities before and after introduction of the bubbles were measured by TCD. RESULTS: Targeted microbubbles enhanced TCD signal intensities from thrombus emboli by up to 13 dB. The bubbles were capable of binding to moving thrombus when injected into the flow circuit in low concentrations ( approximately 36 bubbles per 100 mL) and were retained on the thrombus under pulsatile-flow conditions. Signal intensities from similarly sized pieces of tissue-mimicking material were not enhanced by injection of targeted bubbles. CONCLUSIONS: Injection of appropriately targeted microbubbles significantly enhances TCD detection of circulating thrombus emboli in vitro.

Molecular imaging of human thrombus with novel abciximab immunobubbles and ultrasound.

BACKGROUND AND PURPOSE: Molecular imaging of therapeutic interventions with targeted agents that simultaneously carry drugs or genes for local delivery is appealing. We investigated the ability of a novel microbubble carrier (immunobubble) for abciximab, a glycoprotein IIb/IIIa receptor inhibitor, for ultrasonographic molecular imaging of human clots. METHODS: Human thrombi were incubated with immunobubbles conjugated with abciximab. Control clots were incubated in either saline or with immunobubbles conjugated with nonspecific antibody. We evaluated immunobubble suspensions with variable concentrations of encapsulated gas and measured mean acoustic intensity of the incubated clots. In vivo molecular imaging of human thrombi with abciximab immunobubbles was evaluated in a rat model of carotid artery occlusion. RESULTS: Mean acoustic intensity was significantly higher for abciximab immunobubbles as compared with control immunobubbles under all conditions tested with maximum difference in intensity at a gas volume of 0.2 microL (P=0.0013 for mechanical index 0.05, P=0.0001 for mechanical index 0.7). Binding of abciximab immunobubbles to clots in vitro led to enhanced echogenicity dependent on bubble concentration. In vivo ultrasonic detectability of carotid thrombi was significantly higher for clots targeted with abciximab immunobubbles (P<0.05). Quantification of in vivo contrast enhancement displayed a highly significant increment for abciximab immunobubble-targeted clots compared with nonspecific immunobubble-targeted clots (P<0.0001) and to native clots (P<0.0001). CONCLUSIONS: This study demonstrates the feasibility of using a therapeutic agent for selective targeting in vascular imaging. Abciximab immunobubbles improve visualization of human clots both in vitro and in an in vivo model of acute arterial thrombotic occlusion.

Ultrasound contrast agents for brain perfusion imaging and ischemic stroke therapy.

Stroke is one of the major causes of death and disabilities in industrialized countries. Ultrasound imaging is a largely wide spread bedside technique that is easily accessible and valuable in case of emergency but suffers from the fact that the ultrasound wave has to cross the skull for brain imaging. However, ultrasound contrast agents and new contrast-specific imaging modalities have helped to improve the diagnostic quality of transcranial ultrasonography. This review article surveys and discusses the current state of microbubbles technology and the use of contrast-enhanced transcranial ultrasound for the assessment of brain perfusion. Future aspects and expectations in contrast agent functionality, such as targeting and drug or gene delivery, acceleration of thrombolysis, and imaging technology, are also discussed.

A polydioxanone electrospun valved patch to replace the right ventricular outflow tract in a growing lamb model.

A major issue in congenital heart surgery is the lack of viable right ventricular outflow tract (RVOT) replacement materials. Several biomaterials have been used, with different scaffolds and cells, but they have failed to restore a tri-layered RVOT, and reoperations are often required. We investigated the function, histological changes and potential of growth and tissue regeneration of polydioxanone (PDO) electrospun bioabsorbable valved patches seeded with mesenchymal stem cells (MSCs) in the RVOT of growing lambs. Autologous blood-derived MSCs were labeled with quantum dots and seeded on PDO electrospun valved patches. Those were implanted into the RVOT of 6 growing lambs followed up until 8 months. Results were assessed by echocardiography, magnetic resonance imaging (MRI), histology, immunohistochemistry and biochemical assays. Tissue-engineered RVOT were neither stenotic nor aneurismal and displayed a growth potential, with less fibrosis, less calcifications and no thrombus compared with control polytetrafluoroethylene (PTFE)-pericardial patches. The PDO scaffold was completely degraded and replaced by a viable, three-layered, endothelialized tissue and an extracellular matrix with elastic fibers similar to that of native tissue. Detection of quantum dots at 1 month suggested that at least some of the cells were-derived from the grafted cells. A polydioxanone electrospun tissue-engineered valved transannular patch seems to be a promising device in restoring a living RVOT and could ultimately lead to applications in the treatment of congenital RVOT diseases.

In vivo clot lysis of human thrombus with intravenous abciximab immunobubbles and ultrasound.

Abciximab immunobubbles have been introduced recently for ultrasonographic molecular imaging of human thrombus. This study investigates the potential of using these novel bubbles for enhancing sonothrombolysis. In particular, it addresses the question of whether ligand targeting of bubbles with abciximab improves the effectiveness of lysis with ultrasound. A partial thrombotic occlusion of the right common carotid artery of 16 rats was produced by insertion of human clot material via an external carotid artery catheter. Rats received abciximab immunobubbles, non-specific control immunobubbles or saline intravenously over 30 minutes in combination with pulsed 2 MHz ultrasound. Blood samples were taken at baseline and 5, 10, 20, 30 and 60 minutes after beginning treatment. Human D-dimer levels for quantification of thrombolysis were analysed by ELISA. Only animals treated with abciximab immunobubbles and ultrasound showed a significant increase of D-dimer levels over time (p = 0.043, linear trend p = 0.037), whereas in the other two groups, no significant increase over time was found. Overall, animals in the abciximab immunobubbles group showed higher plasma D-dimer levels than animals treated with non-specific immunobubbles (p = 0.049) and animals treated with ultrasound alone (p = 0.017). In histological sections, thrombi treated with abciximab immunobubbles and ultrasound showed clear signs of disintegration in contrast to thrombi in both control groups. 2 MHz ultrasound in combination with abciximab immunobubbles induces thrombolysis without lytic agents that is superior to insonation of non-specific immunobubbles.

New technology: valve repair using biodegradable rings.

OBJECTIVE: To introduce a new concept in the annuloplasty technology. Although rigid and flexible rings meet the basic needs of adults, they do not preserve the changes in shape and size occurring during the cardiac cycle. If implanted in children, such materials do not allow growth of the native annulus. METHODS: From March 2003 to March 2007, 207 patients underwent mitral and/or tricuspid valve repair implanting polidioxanone biodegradable rings--Bioring. Patients were divided into two groups: Group 1, Adults: n=121. Mean age: 48 years (+/- 19.2). Oldest 85 years. Group 2, Pediatric: n=86. Mean age: 9.6 years (+/- 4.4). Youngest 0.5 years. RESULTS: Group 1, Hospital mortality: 3.3%. Mean follow-up: 26.4 months +/- 15.4. Four patients underwent mitral valve replacement 1, 2, 2 and 4 months post repair. Group 2, Hospital mortality: 1.2%. Mean follow-up: 26.7 months+/-13.4. Seven mitral reoperations within 1 to 24 months, two for valve re-repair, five for valve replacement. CONCLUSIONS: Biodegradable rings remodel the shape, reinforce the repair, restore the function of the atrioventricular valves and maintain the three dimensional dynamic motion and geometry of the mitral and tricuspid valves annulus. Growth potential is preserved in children. Although the biodegradable annuloplasty ring was first designed and developed for a pediatric population, it is currently applied to adult cases. Children with single ventricle and AV valve incompetence are an additional indication. The mid-term results showed that degradation of the device occurred without negative observable consequences. Long-term results should confirm these findings.

Nova tecnologia: valvuloplastias com anéis biodegradáveis / New technology: valve repair using biodegradable rings

OBJETIVO: Introduzir um novo conceito na tecnologia de anuloplastia. Embora anéis rígidos e flexíveis cumpram com as necessidades básicas em adultos, não preservam mudanças na forma e no tamanho ocorridos durante o ciclo cardíaco. Se implantado em crianças, eles não permitem o crescimento do anel nativo. Métodos: De março de 2003 a março de 2007, 207 pacientes submeteram-se ao reparo da valva mitral e/ou tricúspide implantando anéis biodegradáveis de polidioxanona Bioring®. Pacientes foram separados em dois grupos: Grupo 1, Adultos n=121. Idade média: 48 anos (± 19,2). Mais velho 85 anos. Grupo 2, Pediátrico: n=86. Idade média: 9,6 anos (± 4,4). Mais novo 0,5 anos. RESULTADOS: Grupo 1 - mortalidade hospitalar: 3,3 por cento; seguimento médio: 26,4 meses ± 15,4. Quatro pacientes submetidos à substituição da valva mitral 1,2,2 e 4 meses pós-reparo. Grupo 2 - mortalidade hospitalar: 1,2 por cento; seguimento médio: 26,7 meses, ± 13,4. Sete reoperações mitrais entre 1 a 24 meses, duas para novo reparo da válvula, cinco para substituição valvar. CONCLUSÕES: Anéis biodegradáveis remodelam a forma, reforçam o reparo, devolvem a função das valvas atrioventriculares, mantendo a dinâmica tridimensional e geometria dos anéis valvares mitrais e tricuspídeos. Além disso, estes anéis preservam o crescimento potencial em crianças. Embora o anel de anuloplastia biodegradável tenha sido inicialmente desenvolvido para população pediátrica, é atualmente aplicado em adultos. Crianças com ventrículoúnico e incompetências valvares A-V são indicações adicionais. Resultados a médio prazo mostraram que a degradação do produto ocorreu sem conseqüências negativas observáveis. Resultados a longo termo deverão comprovar estes achados.

OBJECTIVE: To introduce a new concept in the annuloplasty technology. Although rigid and flexible rings meet the basic needs of adults, they do not preserve the changes in shape and size occurring during the cardiac cycle. If implanted in children, such materials do not allow growth of the native annulus. METHODS: From March 2003 to March 2007, 207 patients underwent mitral and/or tricuspid valve repair implanting polidioxanone biodegradable rings - Bioring®. Patients were divided into two groups: Group 1, Adults: n=121. Mean age: 48 years (± 19.2). Oldest 85 years. Group 2, Pediatric: n=86. Mean age: 9.6 years (± 4.4). Youngest 0.5 years. RESULTS: Group 1, Hospital mortality: 3.3 percent. Mean follow-up: 26.4 months ± 15.4. Four patients underwent mitral valve replacement 1, 2, 2 and 4 months post repair. Group 2, Hospital mortality: 1.2 percent. Mean follow-up: 26.7 months±13.4. Seven mitral reoperations within 1 to 24 months, two for valve re-repair, five for valve replacement. CONCLUSIONS: Biodegradable rings remodel the shape, reinforce the repair, restore the function of the atrioventricular valves and maintain the three dimensional dynamic motion and geometry of the mitral and tricuspid valves annulus. Growth potential is preserved in children. Although the biodegradable annuloplasty ring was first designed and developed for a pediatric population, it is currently applied to adult cases. Children with single ventricle and AV valve incompetence are an additional indication. The mid-term results showed that degradation of the device occurred without negative observable consequences. Long-term results should confirm these findings.