Virginie Papadopoulou

A critical review of physiological bubble formation in hyperbaric decompression

Bubbles are known to form in the body after scuba dives, even those done well within the decompression model limits. These can sometimes trigger decompression sickness and the dive protocols should therefore aim to limit bubble formation and growth from hyperbaric decompression. Understanding these processes physiologically has been a challenge for decades and there are a number of questions still unanswered. The physics and historical background of this field of study is presented and the latest studies and current developments reviewed. Heterogeneous nucleation is shown to remain the prime candidate for bubble formation in this context. The two main theories to account for micronuclei stability are then to consider hydrophobicity of surfaces or tissue elasticity, both of which could also explain some physiological observations. Finally the modeling relevance of the bubble formation process is discussed, together with that of bubble growth as well as multiple bubble behavior.

Circulatory bubble dynamics: From physical to biological aspects

Bubbles can form in the body during or after decompression from pressure exposures such as those undergone by scuba divers, astronauts, caisson and tunnel workers. Bubble growth and detachment physics then becomes significant in predicting and controlling the probability of these bubbles causing mechanical problems by blocking vessels, displacing tissues, or inducing an inflammatory cascade if they persist for too long in the body before being dissolved. By contrast to decompression induced bubbles whose site of initial formation and exact composition are debated, there are other instances of bubbles in the bloodstream which are well-defined. Gas emboli unwillingly introduced during surgical procedures and ultrasound microbubbles injected for use as contrast or drug delivery agents are therefore also discussed. After presenting the different ways that bubbles can end up in the human bloodstream, the general mathematical formalism related to the physics of bubble growth and detachment from decompression is reviewed. Bubble behavior in the bloodstream is then discussed, including bubble dissolution in blood, bubble rheology and biological interactions for the different cases of bubble and blood composition considered.

Long term effects of recreational SCUBA diving on higher cognitive function.

We investigated long‐term effects of SCUBA diving on cognitive function using a battery of neuropsychometric tests: the Simple Reaction Time (REA), Symbol Digit Substitution (SDS), Digit Span Backwards (DSB), and Hand‐Eye Coordination tests (EYE). A group (n = 44) of experienced SCUBA divers with no history of decompression sickness was compared to non‐diving control subjects (n = 37), as well as to professional boxers (n = 24), who are considered at higher risk of long term neurological damage. The REA was significantly shorter in SCUBA divers compared to the control subjects, and also more stable over the time course of the test. In contrast, the number of digits correctly memorized and reordered (DSB) was significantly lower for SCUBA divers compared to the control group. The results also showed that boxers performed significantly worse than the control group in three out of four tests (REA, DSB, EYE). While it may be concluded that accident‐free SCUBA diving may have some long‐term adverse effects on short‐term memory, there is however, no evidence of general higher cognitive function deficiency.

Decompression induced bubble dynamics on ex vivo fat and muscle tissue surfaces with a new experimental set up.

Vascular gas bubbles are routinely observed after scuba dives using ultrasound imaging, however the precise formation mechanism and site of these bubbles are still debated and growth from decompression in vivo has not been extensively studied, due in part to imaging difficulties. An experimental set-up was developed for optical recording of bubble growth and density on tissue surface area during hyperbaric decompression. Muscle and fat tissues (rabbits, ex vivo) were covered with nitrogen saturated distilled water and decompression experiments performed, from 3 to 0bar, at a rate of 1bar/min. Pictures were automatically acquired every 5s from the start of the decompression for 1h with a resolution of 1.75μm. A custom MatLab analysis code implementing a circular Hough transform was written and shown to be able to track bubble growth sequences including bubble center, radius, contact line and contact angles over time. Bubble density, nucleation threshold and detachment size, as well as coalescence behavior, were shown significantly different for muscle and fat tissues surfaces, whereas growth rates after a critical size were governed by diffusion as expected. Heterogeneous nucleation was observed from preferential sites on the tissue substrate, where the bubbles grow, detach and new bubbles form in turn. No new nucleation sites were observed after the first 10min post decompression start so bubble density did not vary after this point in the experiment. In addition, a competition for dissolved gas between adjacent multiple bubbles was demonstrated in increased delay times as well as slower growth rates for non-isolated bubbles.

Pre-dive Whole-Body Vibration Better Reduces Decompression-Induced Vascular Gas Emboli than Oxygenation or a Combination of Both

Purpose: Since non-provocative dive profiles are no guarantor of protection against decompression sickness, novel means including pre-dive “preconditioning” interventions, are proposed for its prevention. This study investigated and compared the effect of pre-dive oxygenation, pre-dive whole body vibration or a combination of both on post-dive bubble formation. Methods: Six healthy volunteers performed 6 no-decompression dives each, to a depth of 33 mfw for 20 min (3 control dives without preconditioning and 1 of each preconditioning protocol) with a minimum interval of 1 week between each dive. Post-dive bubbles were counted in the precordium by two-dimensional echocardiography, 30 and 90 min after the dive, with and without knee flexing. Each diver served as his own control. Results: Vascular gas emboli (VGE) were systematically observed before and after knee flexing at each post-dive measurement. Compared to the control dives, we observed a decrease in VGE count of 23.8 ± 7.4% after oxygen breathing (p < 0.05), 84.1 ± 5.6% after vibration (p < 0.001), and 55.1 ± 9.6% after vibration combined with oxygen (p < 0.001). The difference between all preconditioning methods was statistically significant. Conclusions: The precise mechanism that induces the decrease in post-dive VGE and thus makes the diver more resistant to decompression stress is still not known. However, it seems that a pre-dive mechanical reduction of existing gas nuclei might best explain the beneficial effects of this strategy. The apparent non-synergic effect of oxygen and vibration has probably to be understood because of different mechanisms involved.

A ternary model of decompression sickness in rats

BACKGROUND Decompression sickness (DCS) in rats is commonly modelled as a binary outcome. The present study aimed to develop a ternary model of predicting probability of DCS in rats, (as no-DCS, survivable-DCS or death), based upon the compression/decompression profile and physiological characteristics of each rat. METHODS A literature search identified dive profiles with outcomes no-DCS, survivable-DCS or death by DCS. Inclusion criteria were that at least one rat was represented in each DCS status, not treated with drugs or simulated ascent to altitude, that strain, sex, breathing gases and compression/decompression profile were described and that weight was reported. A dataset was compiled (n=1602 rats) from 15 studies using 22 dive profiles and two strains of both sexes. Inert gas pressures in five compartments were estimated. Using ordinal logistic regression, model-fit of the calibration dataset was optimised by maximum log likelihood. Two validation datasets assessed model robustness. RESULTS In the interpolation dataset the model predicted 10/15 cases of nDCS, 3/3 sDCS and 2/2 dDCS, totalling 15/20 (75% accuracy) and 18.5/20 (92.5%) were within 95% confidence intervals. Mean weight in the extrapolation dataset was more than 2SD outside of the calibration dataset and the probability of each outcome was not predictable. DISCUSSION This model is reliable for the prediction of DCS status providing the dive profile and rat characteristics are within the range of parameters used to optimise the model. The addition of data with a wider range of parameters should improve the applicability of the model.

A new preclinical ultrasound platform for widefield 3D imaging of rodents

Noninvasive in vivo imaging technologies enable researchers and clinicians to detect the presence of disease and longitudinally study its progression. By revealing anatomical, functional, or molecular changes, imaging tools can provide a near real-time assessment of important biological events. At the preclinical research level, imaging plays an important role by allowing disease mechanisms and potential therapies to be evaluated noninvasively. Because functional and molecular changes often precede gross anatomical changes, there has been a significant amount of research exploring the ability of different imaging modalities to track these aspects of various diseases. Herein, we present a novel robotic preclinical contrast-enhanced ultrasound system and demonstrate its use in evaluating tumors in a rodent model. By leveraging recent advances in ultrasound, this system favorably compares with other modalities, as it can perform anatomical, functional, and molecular imaging and is cost-effective, portable, and high throughput, without using ionizing radiation. Furthermore, this system circumvents many of the limitations of conventional preclinical ultrasound systems, including a limited field-of-view, low throughput, and large user variability.

Oxygen microbubbles improve radiotherapy tumor control in a rat fibrosarcoma model – A preliminary study

Cancer affects 39.6% of Americans at some point during their lifetime. Solid tumor microenvironments are characterized by a disorganized, leaky vasculature that promotes regions of low oxygenation (hypoxia). Tumor hypoxia is a key predictor of poor treatment outcome for all radiotherapy (RT), chemotherapy and surgery procedures, and is a hallmark of metastatic potential. In particular, the radiation therapy dose needed to achieve the same tumor control probability in hypoxic tissue as in normoxic tissue can be up to 3 times higher. Even very small tumors (<2–3 mm3) comprise 10–30% of hypoxic regions in the form of chronic and/or transient hypoxia fluctuating over the course of seconds to days. We investigate the potential of recently developed lipid-stabilized oxygen microbubbles (OMBs) to improve the therapeutic ratio of RT. OMBs, but not nitrogen microbubbles (NMBs), are shown to significantly increase dissolved oxygen content when added to water in vitro and increase tumor oxygen levels in vivo in a rat fibrosarcoma model. Tumor control is significantly improved with OMB but not NMB intra-tumoral injections immediately prior to RT treatment and effect size is shown to depend on initial tumor volume on RT treatment day, as expected.

Quantitative assessment of angiogenic microvasculature using Ultrasound multiple scattering with microbubble contrast agents

In tumors, angiogenesis (formation of new blood vessels) is established as a biomarker of malignancy. A random, isotropic, high-density vessel network is linked to tumor invasiveness. Ultrasound quantification of angiogenic micro-architecture could help increase the specificity of ultrasound for cancer diagnosis. We exploit multiple scattering by microbubbles populating angiogenic networks to characterize an effective medium diffusivity via the diffusion constant (D). The inter-element response matrix is acquired using an L11-4v linear array transducer operating at 7.8 MHz. D is computed from the time evolution of the incoherent contribution to the backscattered intensity in the near field. D is measured in fibrosarcoma tumors subcutaneously implanted in rats (n = 16), and in control, healthy tissue (n = 18). D is measured for two different orientations (Coronal and Transverse) and the anisotropy of the microvasculature is evaluated via the ratio of the D values obtained in the two different orientations. D was found significantly different between control (1.38 ± 0.51 mm2/μs) and tumor (0.65 ± 0.27 mm2/μs) (p<0.01) and anisotropy of the angiogenic network was observed in control cases (1.62 ± 0.911). For further validation, these results were corroborated with vascular density measurements from acoustic angiography data, confirming increased vessel density in tumors compared to controls.In tumors, angiogenesis (formation of new blood vessels) is established as a biomarker of malignancy. A random, isotropic, high-density vessel network is linked to tumor invasiveness. Ultrasound quantification of angiogenic micro-architecture could help increase the specificity of ultrasound for cancer diagnosis. We exploit multiple scattering by microbubbles populating angiogenic networks to characterize an effective medium diffusivity via the diffusion constant (D). The inter-element response matrix is acquired using an L11-4v linear array transducer operating at 7.8 MHz. D is computed from the time evolution of the incoherent contribution to the backscattered intensity in the near field. D is measured in fibrosarcoma tumors subcutaneously implanted in rats (n = 16), and in control, healthy tissue (n = 18). D is measured for two different orientations (Coronal and Transverse) and the anisotropy of the microvasculature is evaluated via the ratio of the D values obtained in the two different orientations....

Adaptation of the acoustic angiography technique for use with a capacitive micromachined ultrasound transducer (CMUT)

Though a fairly new technology, CMUTs present many advantages over traditional piezoelectric transducers, including wider frequency bandwidths, easier integration with circuitry, and cheaper and easier production. The wide frequency bandwidth of CMUTs makes them ideal for multi-frequency ultrasound (US) applications in particular. In this work, we present a CMUT-specific version of the dual-frequency superharmonic imaging technique known as “acoustic angiography” (AA). This contrast US method combines a low frequency transmit with a high frequency receive to create microvascular images, but two-element prototypes are required to do so. These probes are confocally aligned and must be mechanically scanned to create an image. Here, this technique has been optimized for use with a single CMUT array.