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DOI: 10.1148/radiol.2241011352
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(Radiology 2002;224:253-257.)
© RSNA, 2002

Experimental Studies

Mechanism of Parenchymal Enhancement of the Liver with a Microbubble-based US Contrast Medium: An Intravital Microscopy Study in Rats1

Yuko Kono, MD, Gregory C. Steinbach, PhD2, Thomas Peterson, BA, Geert W. Schmid-Schönbein, PhD and Robert F. Mattrey, MD

1 From the Departments of Radiology (Y.K., G.C.S., T.P., R.F.M.) and Bioengineering (G.W.S.S.), University of California, San Diego. From the 2000 RSNA scientific assembly. Received August 9, 2001; revision requested September 28; revision received December 5; accepted January 7, 2002. Supported in part by R01-CA36799 and Alliance Pharmaceutical Corporation. Address correspondence to R.F.M., MRI Institute, 410 Dickinson St, San Diego, CA 92103 (e-mail: rmattrey@ucsd.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To investigate the mechanism of prolonged contrast material enhancement of the liver observed with the lipid-shell ultrasonographic (US) contrast agent AF0150, with use of intravital microscopy.

MATERIALS AND METHODS: Eight Sprague-Dawley rats were used. Six received fluoroscent microspheres to label the Kupffer cells; two were used as controls. The edge of the middle lobe of the liver was transilluminated with white light. Fluorescent microspheres were observed under fluorescence light. After injection of AF0150, behavior of microbubbles was observed for 6 minutes while viewing a single high-power field. Multiple other fields were then assessed for stationary bubbles and their relation to Kupffer cells. The number of bubbles in motion, aggregated, stationary, and associated with labeled cells were counted.

RESULTS: Of 590 bubbles, 34 (5.8%) became stationary and 556 (94.2%) kept moving. Of the 34 stationary microbubbles, 21 dislodged within 30 seconds. Microbubbles were homogeneously distributed throughout the lobule, in contrast to the dominant periportal distribution of the labeled Kupffer cells. Among 83 stationary bubbles observed from all fields of view, only 14 (17%) were associated with fluorescent-labeled cells.

CONCLUSION: The late parenchymal liver enhancement effect of AF0150 is likely not related to Kupffer-cell uptake, but rather to a mechanical slowdown within the sinusoids.

© RSNA, 2002

Index terms: Experimental study • Liver, US, 761.12988 • Microbubbles, 761.12988 • Ultrasound (US), contrast media, 761.12988


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Currently, a number of microbubble-based ultrasonographic (US) contrast agents are approved or are in the process of approval by the U.S. Food and Drug Administration. These microbubbles enhance the visualization of the vascular system and enhance solid organs to enable detection or characterization of defects or lesions (1,2).

The liver harbors a variety of primary benign and malignant lesions, as well as metastatic deposits; therefore, its assessment is critical in the staging of many malignancies to assess prognosis or guide patient care. The dual blood supply of the liver has aided computed tomography (CT) and magnetic resonance (MR) imaging in lesion depiction by providing an opportunity to image tumors during their preferential enhancement while the contrast medium is passing through the hepatic arterial system. The dynamic triple-phase imaging technique used with CT and MR imaging also adds characterization capability to aid in distinguishing benign from malignant lesions. By using AF0150 (Imavist; Alliance Pharmaceutical, San Diego, Calif), a lipid-shell microbubble contrast agent, we showed that microbubbles can be observed in real time as they sequentially fill the hepatic arteries, portal veins, and then the hepatic parenchyma, bringing to US the pharmacodynamic data available for CT and MR imaging (3). In that study, we observed a late hepatic enhancement phase that persisted beyond the vascular enhancement phase and was not observed in tumors, suggesting specific liver entrapment (3). We further showed in an animal model that observing the dynamics of the US contrast agent and the late parenchymal phase significantly increased the conspicuity of tumors, potentially expanding the role of US in tumor detection and characterization (4).

This late-phase enhancement (3–5 minutes after injection) has been exploited to improve lesion conspicuity and detection in human subjects by using stimulated acoustic emission (5), as well as pulse inversion gray-scale harmonic imaging (6). In these studies, the authors speculated that the agent SH U 508A (Levovist; Schering, Berlin, Germany) is taken up by Kupffer cells, providing specific liver enhancement. This hypothesis was supported by the fact that stiff-shelled microbubbles SH U 563A (Sonovist; Schering) and NC100100 (Nycomed-Amersham, Oslo, Norway) have been shown within Kupffer cells (7,8) and that SH U 508A enhances the liver and spleen but not kidneys in the late phase. An alternate hypothesis exists, however, in that the liver and spleen contain sinusoids, whereas liver lesions and kidneys do not. The mean diameter of microbubbles is 2–3 µm, limiting their distribution to the vascular space. Because of their buoyancy, the bubbles rise to a nondependent position within stagnant fluids or infusion tubing, requiring frequent mixing. We speculated that because of the complex sinusoidal structure of the liver where blood flow is slow, the bubbles rise within sinusoidal pools and stagnate in the vascular system of these organs, resulting in prolonged enhancement.

Understanding the mechanism of this prolonged liver enhancement can provide useful information in the design of future contrast agents. More important, data would be available to assess the pathophysiologic mechanism of potential side effects and efficacy when imaging the liver. The behavior of microbubbles has been investigated with intravital microscopy in the cheek pouch (9) and in the mesentery (10). Sonicated albumin microbubble behavior is known to be similar to that of red blood cells in normal tissue. Although microbubbles have been shown to adhere to activated endothelial cells and leukocytes (11,12), adherence to normal endothelial cells is uncommon (9).

Because the mechanism of liver entrapment is known only for the stiff-shelled agents, and because the late liver parenchymal phase occurs with many late-generation perfluorocarbon-based agents, we aimed to investigate the mechanism of prolonged liver enhancement observed with the lipid-shell agent AF0150, with use of intravital microscopy.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Intravital Microscopy
Experiments were performed on eight Sprague-Dawley rats weighing 160–215 g (average, 180 g). Six rats were given 0.05 mL of fluorescent microspheres (4.55 x 1010 particles per milliliter, 0.941 µm ± 0.014 size, Fluoresbrite plain YG microspheres; Polysciences, Warrington, Pa) in the tail vein 24 hours before study, to label the Kupffer cells (13). The other two rats served as controls. A day later, rats were anesthetized with a 5:1 cocktail of ketamine and acepromazine, and the middle lobe of the liver was exteriorized. With the rat in the left lateral decubitus position, the liver was placed onto a slanted quartz crystal that served as a microscopy stage. The exposed liver lobe was covered with a small piece of plastic wrap to keep the liver moist and to reduce liver respiratory motion. Krebs-Henseleit solution (30.84 g of NaCl, 1.40 g of KCl, 1.16 g of CaCl2, 1.20 g of MgSO4, and 7.24 g of NaHCO3 in 4 L of distilled water) at 37°C was dripped onto the liver to keep the liver moist and warm and to provide the fluid necessary for the water immersion objectives. In addition, the microscopy stage was heated to 37°C to maintain animal warmth. The study was reviewed and approved by the institutional animal subject committee at our institution and was conducted in accordance with National Institutes of Health guidelines.

A standard intravital microscope (Technical Instrument, San Francisco, Calif) equipped with Leica optics was used with water immersion objectives of x25 (Leitz Wetzlar) and x60 (Olympus LUMplanFl). Transillumination was provided by a halogen light source (250 W) and a direct current power supply (6433B; Hewlett-Packard, Rockaway, NJ). The light was focused onto the area of interest with a focusable condenser placed in the light path. Epillumination was used to fluoresce the fluorescent particles with filtered light that was generated by a 200-W mercury lamp. The filtration system was a quartz collector and a heat filter (model KG-2; Carl Zeiss, Thornwood, NY) that allowed a 450–490-nm band to illuminate the sample. The light emitted by the sample was filtered to view the 520-nm band, allowing recognition of the fluorescent particles.

Imaging Protocol
AF0150 (Imavist; Alliance Pharmaceutical) is a microbubble-based US contrast agent that encapsulates perfluorohexane gas in a thin lipid shell that was designed to be easily deformed to promote nonlinear oscillations when insonated. At constitution with 10 mL of water, each milliliter of product contains a mean of 9.8 x 108 microbubbles with a mean diameter of 2–3 µm. Two to three separate injections of 1.5–3.0 mL (1.5–3.0 x 109 microbubbles) of AF0150 were infused over 30–60 seconds through a 25-gauge needle placed in the tail vein. With use of a x60 objective, a single field of 120 x 150 µm located at the edge of the liver was observed during 6 minutes after injection. At the end of the 6-minute observation period, the stage was moved to other parts of the liver to obtain snapshots of at least two other high-power fields. On several occasions during the 6-minute observation period and over other fields, the light source was switched to locate the labeled Kupffer cells. The entire session was recorded on S-VHS tape for off-site analysis.

In total, we gave 22 injections at an average dose of 2.55 mL per injection. Real-time observation was collected from 22 fields, and snapshot views were obtained of over 40 fields.

Data Collection and Analysis
From the fields observed in real time, the number of microbubbles that were in motion, aggregated, or stationary were counted. The time (in seconds) after injection when microbubbles came into the field of view was recorded. When microbubbles became stationary, their relationship to the fluorescent-labeled cells was noted. The behavior of all visible microbubbles was monitored to determine their fate. The time spent in the field of view was recorded in seconds. From the snapshots obtained from other fields, the number of stationary microbubbles and their relationship to the fluorescent-labeled cells was recorded.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Fluorescent microsphere distribution was patchy and was mainly in the periportal zone (14,15) (Fig 1). Microbubbles were clearly seen with white light transillumination (Fig 2). Microbubbles became visible in the sinusoids approximately 5–10 seconds after the start of infusion. The number of microbubbles peaked between 60 and 90 seconds after injection, with very few microbubbles seen beyond 4–5 minutes after injection (Fig 3a).



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  		Figure 1a. (a) Distribution of fluorescent microspheres. (Original magnification, x25; fluorescent light.) (b) Fluorescent microspheres showed patchy distribution around the periportal area recognized under white light. (c) Schematic of a and b. Fluorescent microspheres are seen around the terminal portal vein (TPV), periportal area.

 


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  		Figure 1b. (a) Distribution of fluorescent microspheres. (Original magnification, x25; fluorescent light.) (b) Fluorescent microspheres showed patchy distribution around the periportal area recognized under white light. (c) Schematic of a and b. Fluorescent microspheres are seen around the terminal portal vein (TPV), periportal area.

 


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  		Figure 1c. (a) Distribution of fluorescent microspheres. (Original magnification, x25; fluorescent light.) (b) Fluorescent microspheres showed patchy distribution around the periportal area recognized under white light. (c) Schematic of a and b. Fluorescent microspheres are seen around the terminal portal vein (TPV), periportal area.

 


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  		Figure 2. Formation and disassociation are shown in these six frames acquired over 16 seconds. Note that light diffraction at the edge of the bubbles allows their visualization. (a) Association of two bubbles occurred when a small bubble (arrowhead) came in contact with a larger bubble. (b) The small bubble rotated around (arrowhead) the larger bubble. A third bubble (c) approached (arrow) and (d) joined them, forming a three-bubble association. The original small bubble then (e) dislodged and (f) moved on (arrowhead). None of these bubbles was associated with fluorescent-labeled cells (not shown). (Original magnification, x60; white light.)

 


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  		Figure 3a. (a) Graph shows number of moving versus stationary AF0150 microbubbles over the observed period. Most microbubbles were in motion, and the number peaked at 60-90 seconds after injection. Only a few bubbles became stationary. (b) Pie charts show distribution and fate of observed bubbles.

 


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  		Figure 3b. (a) Graph shows number of moving versus stationary AF0150 microbubbles over the observed period. Most microbubbles were in motion, and the number peaked at 60-90 seconds after injection. Only a few bubbles became stationary. (b) Pie charts show distribution and fate of observed bubbles.

 
Thirty-four (5.8%) of 590 microbubbles that were counted during the 6-minute observation period became stationary. Of those 34 stationary microbubbles, 21 (62%) dislodged within 30 seconds and left the field of view. Of the remaining 13 microbubbles, two dislodged after 30 seconds, four shrunk and disappeared, one shrunk but remained visible at 6 minutes, and six were lost to observation (Fig 3b). Three of the 34 bubbles that became stationary were associated with fluorescent-labeled cells. One of these dislodged after 12 seconds, one shrunk and disappeared after 3 minutes, and one was still stationary at the end of the observation period.

From the snapshots acquired from other fields, we counted 83 stationary bubbles; 14 (17%) of these were associated with fluorescent-labeled cells. Further, the microbubbles were distributed homogeneously throughout the lobule, unlike the periportal distribution of the fluorescent microspheres.

Forty-one groups of two to eight microbubbles were associated together, accounting for 105 of the 590 microbubbles observed. Thirty-six of these 41 groups remained in motion, two disassociated, two dislodged after 2 and 4 seconds of observation, respectively, and one was lost during the observation period.

Microbubble behavior between the six rats given fluorescent microspheres and the two control rats was similar, with comparable relative counts of stationary versus nonstationary microbubbles. None of the microbubbles observed increased in size during the observation period.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
Kupffer cells, the resident liver macrophages, constitute 31% of the sinusoidal cells (14). They are more numerous (43%) in the periportal zone of the lobule than in the middle (28%) or central (29%) zones (14). Latex particles label approximately 64% of all Kupffer cells (14). In addition to being more numerous, the periportal Kupffer cells are larger, have more lysosomes (15), and take up more particles than do the middle- or central-zone Kupffer cells (13,14). Similar to published data, our results also showed a periportal predominance of the fluorescent label. Although latex particles do not label all Kupffer cells, they are considered a reasonable index of phagocytosis (13–15).

Phagocytosis is influenced by particle size and surface properties that affect adhesion, such as hydrophobic or positively charged particle surface (16,17). Unless the microbubble is adherent, engulfing an elastic deformable microbubble may be more difficult than engulfing one with a stiff shell. Therefore, some formulations would be better phagocytosed than others. It is apparent from the current study that if AF0150 is phagocytosed, it is at a minimal level and cannot by itself account for the late-phase effect observed after microbubbles clear the vascular space.

Albumin- and lipid-encapsulated microbubbles have been shown to adhere to activated endothelial surfaces (11,12,18) and to become phagocytosed by white blood cells (19). In the current study, normal rats were used because endothelial activation is not expected and late-phase liver enhancement with US is consistently observed in normal and tumor-containing livers. We do not believe that endothelial activation and phagocytosis can explain the late-phase enhancement of the liver. The dominant population of microbubbles observed in the current study (94.2%) remained in motion during the 6-minute observation period that included the late phase. Of the bubbles that became stationary, most were not associated with the labeled cells and also most moved on within 30 seconds, indicating that they were not phagocytosed but rather slowed mechanically. Further, stationary bubbles were homogeneously distributed throughout the lobule, whereas the labeled cells were concentrated in the periportal zone.

Microbubbles commonly layer in the syringe and tubing, which requires constant mixing, particularly during slow infusions. On the basis of our observations in the current study, indicating that few bubbles become stationary and even fewer become associated with Kupffer cells, we believe that the late liver enhancement phase with AF0150 is most likely a transient mechanical slowdown of the microbubble in the sinusoids, owing to the slow flow that is unable to push them along.

Two observations in the current study are worthy of mention to exclude two possible mechanisms of late-phase enhancement. The first is that none of the bubbles increased in size and lodged in the sinusoids. In fact, four microbubbles that became stationary shrank and disappeared over a few minutes. Although they were not associated with labeled cells, their association and potential phagocytosis by an unlabeled phagocyte cannot be excluded, since they shrank rather than dislodged. The second is that 41 groups of two to eight microbubbles were observed, and nearly all moved through the sinusoids without blocking flow or becoming stationary. Further, microbubbles approximated and dissociated under observation, indicating that the association is weak. We believe that aggregation likely occurred because of the very high dose given, which was approximately 25 times the maximum clinical dose to allow us to observe bubbles in the very small field of view of 120 x 150 x 3–5 µm.

Iodinated lipid emulsions for CT contrast media are phagocytosed by Kupffer cells, as was observed with intravital and electron microscopy (20). In that study, the phagocytosed lipid emulsion particles increased the size of Kupffer cells, obstructing sinusoidal flow. No effect on sinusoidal flow was observed in the current study.

In summary, results of the current study showed that the late-phase (3–5 minutes) enhancement observed with AF0150 is not related to Kupffer cell uptake, bubble growth, or aggregation that causes the bubbles to lodge in the sinusoids. The late-phase enhancement is most likely caused by transient mechanical slowdown of microbubbles as they traverse the complex sinusoidal network.

Practical application: The observation that the lipid-based agent AF0150 is not phagocytosed but is rather slowed in the sinusoids provides three practical applications: (a) The opportunity to increase entrapment can be achieved by altering the shell to promote phagocytosis, (b) it explains the mechanism of enhancement of hemangiomas that contain sinusoids and the lack of enhancement of metastases that do not, and (c) it suggests that potential side effects that could be associated with phagocytosis will likely not occur.


   FOOTNOTES
 
2 Current address: Department of Orthopedic Surgery, University of California, San Diego. Back

Author contributions: Guarantors of integrity of entire study, Y.K., R.F.M.; study concepts, Y.K., R.F.M.; study design, all authors; literature research, Y.K.; experimental studies, Y.K., G.C.S., T.P.; data acquisition and analysis/interpretation, Y.K., G.C.S.; manuscript preparation, definition of intellectual content, editing, and revision/review, Y.K., R.F.M.; manuscript final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 

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  6. Albrecht T, Hoffmann CW, Schettler S, et al. Improved detection of liver metastases with phase inversion imaging during the liver-specific phase of the ultrasound contrast agent Levovist. Eur Radiol 1999; 9(suppl 3):S388.
  7. Bauer A, Blomley M, Leen E, et al. Liver-specific imaging with SHU 563A: diagnostic potential of a new class of ultrasound contrast media. Eur Radiol 1999; 9(suppl 3):S349-S352.
  8. Marelli C. Preliminary experience with NC100100, a new ultrasound contrast for intravenous injection. Eur Radiol 1999; 9(suppl 3):S343-S346.
  9. Keller NW, Segal SS, Kaul S, et al. The behavior of sonicated albumin microbubbles within the microcirculation: a basis for their use during myocardial contrast echocardiography. Circ Res 1989; 65:458-467.[Abstract/Free Full Text]
  10. Feinstein SB, Shah PM, Bing RJ, et al. Microbubble dynamics visualized in the intact capillary circulation. J Am Coll Cardiol 1984; 4:595-600.[Abstract]
  11. Villanueva FS, Jankowski RJ, Manaugh C, et al. Albumin microbubble adherence to human coronary endothelium: implication for assessment of endothelial function using myocardial contrast echocardiography. J Am Coll Cardiol 1997; 30:689-693.[Abstract]
  12. Lindner JR, Coggins MP, Kaul S, et al. Microbubble persistence in the microcirculation during ischemia/reperfusion and inflammation is caused by integrin- and complement-mediated adherence to activated leukocytes. Circulation 2000; 101:668-675.[Abstract/Free Full Text]
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  18. Villanueva FS, Jankowski RJ, Klibanov S, et al. Microbubbles targeted to intracellular adhesion molecule-1 bind to activated coronary artery endothelial cells. Circulation 1998; 98:1-5.[Abstract/Free Full Text]
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