INTERFACIAL MECHANICS IN INTRAVASCULAR GAS EMBOLISM
Principal Investigator: David Eckmann
Affiliation: University of Pennsylvania
Abstract: Vital organ blood flow can be compromised by microvascular gas embolism that occurs during surgery, endoscopic procedures, and in decompression sickness. The associated morbidity and mortality carry considerable human and economic impact. The pathophysiology of gas lesion disease has been studied little and is poorly understood. The initiating events involve bubble lodging within the vasculature. The molecular mechanical basis of bubble adhesion to the vessel wall causing blood flow obstruction is unknown. Our preliminary experiments suggest that blood flow obstruction is caused by adhesion of the bubble surface to the endothelial glycocalyx. Our global hypothesis is that surface-surface adhesion interactions between the endothelial glycocalyx and the bubble interface control bubble lodging, and thus determine microcirculatory blood flow and resultant organ injury. We will test this hypothesis via four Specific Aims. To identify determinants of bubble adhesion to the vessel wall, we will use in vivo and in vitro methods and biomimetic glycocalyx constructs. Once the molecular basis of adhesion is identified, we predict that modulation of adhesion by administration of (1) surfactants (a polydimethylsiloxane, a nonionic polyol, and a perfluorocarbon) targeted to bubble-blood interfaces and (2) compounds that modify the endothelial surface layer (air stripping, degradation by Ox-LDL and Heparinase), will alter obstruction of blood flow and development of injury in embolized tissue and organs. Experimental methods will include neurobehavioral assessment, brain microdialysis, histopathology, and transcript profiling in a rat model of middle cerebral artery gas embolism, intravital microscopy in rat cremaster muscle, and measurement of bubble adhesion force in excised microvessels and in microcapillary tubes lined with synthetic endothelial surface layers. The use of preclinical novel pharmacological interventions in the proposed research will enable identification of potential therapeutic targets to reduce bubble adhesion and treat gas embolism. The only clinical alternative is hyperbaric therapy, which requires patient transport to a chamber for postembolism treatment, and is therefore generally used only in catastrophic cases.
Funding Period: 1998-12-01 - 2008-02-29
more information: NIH RePORT
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Department of Anestthesia, The University of Pennsylvania, PA 19104, USA
Dermatol Surg 31:636-43. 2005..Intravenous microfoam sclerotherapy solutions can potentially cause cerebrovascular arterial embolization...
- A quantitative and selective chromatography method for determining coverages of multiple proteins on surfacesMichela Ombelli
Department of Anesthesia, University of Pennsylvania, 319B John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104, USA
J Chromatogr B Analyt Technol Biomed Life Sci 826:198-205. 2005..Relative to silicon, the dextranized surfaces were found to strongly inhibit protein adsorption, decreasing BSA and Fg coverages by 76 and 60%, respectively...
- Dextran functionalized surfaces via reductive amination: morphology, wetting, and adhesionDavide Miksa
Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, 19104, USA
Biomacromolecules 7:557-64. 2006..Overall, film morphology and wetting behavior were relatively invariant with grafting density, confirming the method's robustness for preparing biomimetic coatings with consistent properties...
- Influence of endothelial glycocalyx degradation and surfactants on air embolism adhesionDavid M Eckmann
Department of Anesthesiology and Critical Care, Institute for Medicine and Engineering, The University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Anesthesiology 105:1220-7. 2006..The authors tested the hypothesis that exogenous surfactants delivered intravascularly have differential effects on the rate of restoration of blood flow after heparinase-induced degradation of the endothelial glycocalyx...
- Gas embolism and surfactant-based intervention: implications for long-duration space-based activityDavid M Eckmann
Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA
Ann N Y Acad Sci 1077:256-69. 2006..Special consideration is given to modeling the transport and hydrodynamic interactions associated with surfactant-based intervention...
- Dose- and time-dependent liquid sclerosant effects on endothelial cell deathShunji Kobayashi
Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Dermatol Surg 32:1444-52. 2006..At low sclerosant concentrations, cell viability was maintained beyond the recording time of the experiment. The timing of endothelial cell death is predictable based on sclerosant concentration during exposure...
- Flow dynamics, binding and detachment of spherical carriers targeted to ICAM-1 on endothelial cellsAndres J Calderon
Department of Anesthesiology and Critical Care, University of Pennsylvania Medical School, Philadelphia, PA, USA
Biorheology 46:323-41. 2009..This is further supported by theoretical modeling. These results will guide vascular targeting of drug carriers via rational design of experimentally tunable parameters...