| 1. |
- Ahmed, Mona, et al.
(författare)
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Cellular Uptake of Plain and SPION-Modified Microbubbles for Potential Use in Molecular Imaging
- 2017
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Ingår i: Cellular and Molecular Bioengineering. - : SPRINGER. - 1865-5025 .- 1865-5033. ; 10:6, s. 537-548
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Tidskriftsartikel (refereegranskat)abstract
- Both diagnostic ultrasound (US) and magnetic resonance imaging (MRI) accuracy can be improved by using contrast enhancement. For US gas-filled microbubbles (MBs) or silica nanoparticles (SiNPs), and for MRI superparamagnetic or paramagnetic agents, contribute to this. However, interactions of MBs with the vascular wall and cells are not fully known for all contrast media. We studied the in vitro interactions between three types of non-targeted air-filled MBs with a polyvinyl-alcohol shell and murine macrophages or endothelial cells. The three MB types were plain MBs and two types that were labelled (internally and externally) with superparamagnetic iron oxide nanoparticles (SPIONs) for US/MRI bimodality. Cells were incubated with MBs and imaged by microscopy to evaluate uptake and adhesion. Interactions were quantified and the MB internalization was confirmed by fluorescence quenching of non-internalized MBs. Macrophages internalized each MB type within different time frames: plain MBs 6 h, externally labelled MBs 25 min and internally labelled MBs 2 h. An average of 0.14 externally labelled MBs per cell were internalized after 30 min and 1.34 after 2 h; which was 113% more MBs than the number of internalized internally labelled MBs. The macrophages engulfed these three differently modified new MBs at various rate, whereas endothelial cells did not engulf MBs. Polyvinyl-alcohol MBs are not taken up by endothelial cells. The MB uptake by macrophages is promoted by SPION labelling, in particular external such, which may be important for macrophage targeting.
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| 2. |
- Barrefelt, Åsa, et al.
(författare)
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DYNAMIC MR IMAGING, BIODISTRIBUTION AND PHARMACOKINETICS OF POLYMER SHELLED MICROBUBBLES CONTAINING SPION
- 2014
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Ingår i: NANO. - 1793-2920. ; 9:6, s. 1450069-
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Tidskriftsartikel (refereegranskat)abstract
- Magnetic Resonance Imaging (MRI) is a noninvasive diagnostic method that provides information on morphological and physiological changes of the internal organs over time. Imaging and measurements can be repeated on the same subject, thereby reducing inter-individual variability effects and hence the number of subjects required. A potential MRI contrast agent consisting of microbubbles embedded with superparamagnetic iron oxide nanoparticles (SPION) in the shell (SPION MBs) was injected intravenously into rats to determine their biodistribution and pharmacokinetics using MR imaging. Agarose phantoms containing SPION MBs were scanned using 3 T MRI to construct a standard curve. Rats were injected with SPION MBs, free SPION or plain MBs and scanned dynamically at 3 T using a clinical MR scanner. The relaxation rate (R2*) was studied over time as a measure of the iron oxide concentrations to enable calculation of the pharmacokinetic parameters. The kinetics of SPION MBs in the liver was fitted to a one-compartment model. Furthermore, the biological fate of SPION MBs was examined via a histological survey of tissue samples using Perls' Prussian blue staining and immunohistochemistry (IHC). 1.2 h after injection of SPION MBs, T2* of the liver had decreased to its minimum. The elimination half-life of SPION MBs was 598.2 +/- 97.3 h, while the half-life for SPION was 222.6 +/- 26.4 h. Moreover, our study showed that SPION MBs were taken up by the macrophages in the lungs, spleen and liver. MBs labeled with SPION can be used for MR imaging. Moreover, MRI is a reliable and noninvasive tool that can be utilized in pharmacokinetic investigations of future contrast agents using SPION MBs and SPION in the rat.
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| 3. |
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| 4. |
- Brismar, Torkel B., et al.
(författare)
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Magnetite Nanoparticles Can Be Coupled to Microbubbles to Support Multimodal Imaging
- 2012
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Ingår i: Biomacromolecules. - : American Chemical Society (ACS). - 1525-7797 .- 1526-4602. ; 13:5, s. 1390-1399
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Tidskriftsartikel (refereegranskat)abstract
- Microbubbles (MBs) are commonly used as injectable ultrasound contrast agent (UCA) in modern ultrasonography. Polymer-shelled UCAs present additional potentialities with respect to marketed lipid-shelled UCAs. They are more robust; that is, they have longer shelf and circulation life, and surface modifications are quite easily accomplished to obtain enhanced targeting and local drug delivery. The next generation of UCAs will be required to support not only ultrasound-based imaging methods but also other complementary diagnostic approaches such as magnetic resonance imaging or computer tomography. This work addresses the features of MBs that could function as contrast agents for both ultrasound and magnetic resonance imaging. The results indicate that the introduction of iron oxide nanoparticles (SPIONs) in the poly(vinyl alcohol) shell or on the external surface of the MBs does not greatly decrease the echogenicity of the host MBs compared with the unmodified one. The presence of SPIONs provides enough magnetic susceptibility to the MBs to accomplish good detectability both in vitro and in vivo. The distribution of SPIONs on the shell and their aggregation state seem to be key factors for the optimization of the transverse relaxation rate.
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| 5. |
- Capece, Sabrina, et al.
(författare)
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A general strategy for obtaining biodegradable polymer shelled microbubbles as theranostic devices
- 2013
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Ingår i: Chemical Communications. - 1359-7345 .- 1364-548X. ; 49:51, s. 5763-5765
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Tidskriftsartikel (refereegranskat)abstract
- Fabrication of multifunctional ultrasound contrast agents (UCAs) has been recently addressed by several research groups. A versatile strategy for the synthesis of UCA precursors in the form of biodegradable vesicles with a biocompatible crosslinked polymer shell is described. Upon ultrasound irradiation, acoustic droplet vaporization transforms such particles into microbubbles behaving as UCAs. This proof of concept entails the features of a potential theranostic microdevice.
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| 6. |
- Capese, Sabrina, et al.
(författare)
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A general strategy for the obtainment of biodegradable polymer shelled microbubbles as theranostic device
- 2013
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Konferensbidrag (refereegranskat)abstract
- IntroductionFabrication of multifunctional ultrasound contrast agents (UCAs) has been addressed by many research groups.1,2 Recently a poly(vinyl alcohol) shelled microbubble 3 has shown a remarkable chemical and physical stability and versatility for the surface functionalization, leading to a platform for multimodality imaging (ultrasounds, magnetic resonance, single photon emission computer tomography) and targeting inflammation and tumours4. In this contribution we present a new strategy for the synthesis of UCAs precursors in the form of vesicles with a biodegradable crosslinked polymer shell.MethodsDeposition of methacryloyl-derivative of hydrophilic and biodegradable polymers as dextran (DexMA50) or hyaluronic acid (HAMA30) on a lipid vesicle with a liquid perfluoropentane core, 5,6 followed by a photopolymerization of the methacrylate moiety allows the obtainment of polymer shelled vesicles.ResultsLipid shelled vesicles with a perfluorocarbon (PFC) core (Figure 1a) undergo an acoustic droplet vaporization (ADV),7 upon ultrasounds (US) irradiation, transforming such particles into ultrasound effective microbubbles (Fig 1b). The process is reversible as the US are switched off (Fig 1c). In the “microbubble” state, i.e. during US irradiation, the system is echogenic at low mechanical index, allowing their use as UCAs. In this contribution we show that additional functions can be implemented into the microbubbles. For example, we demonstrated the possibility to obtain shells with a thermoreversible behaviour.ConclusionsThis new class of polymer shelled vesicles/microbubbles entails features desired in a potential theranostic microdevice.
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| 7. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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Acoustic properties of polymer-shelled ultrasound contrast agents. Bulk volume vs. microcapillary
- 2009
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Ingår i: 16th International Congress on Sound and Vibration 2009, ICSV 2009. - Krakow. - 9781615677368 ; , s. 2515-2522
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Konferensbidrag (refereegranskat)abstract
- The focus of contrast-enhanced ultrasound research has developed beyond detecting the blood pool to new areas such as perfusion imaging, drug and gene therapy, and targeted imaging. Polymer-shelled microbubbles are proposed as a new generation of ultrasound contrast agents (UCAs) which fulfil the requirements of these applications. With a shelf-life of several months and possibility to conjugate pharmacological molecules to their surface, these UCAs will allow not only to enhance the contrast of ultrasound images, but also to function as carriers of drugs to be delivered locally. In this study, the results of an experimental investigation of three types of UCAs stabilized by thick poly vinyl alcohol (PVA) shell are presented. These UCAs are synthesized from a PVA aqueous solution under varied pH values and temperature. The UCAs differ from each other in their average diameter, shell thickness and polydispersity. Knowledge of the peak negative pressure at which the solid shell fractures is paramount for a proper use of UCAs. Therefore, the dependence of this quantity on temperature and number of cycles in the incident pulse is examined. Much of the blood volume resides in the microcirculation, with capillaries playing a particularly important role in patho-physiology and drug delivery. In this sense in vitro characterization of the UCAs oscillation was moved from bulk volume to the capillary scale, where tissue-bubble interaction takes place. The main conclusion to be drawn from these results is that the shell of the UCAs begin to fracture at values of mechanical index (MI) approved for clinical applications. The fatigue, i.e. the accumulation of damage within the shell of the UCAs, is found to play an important role in fracturing the shell. Finally adhesion of the UCAs to the elastic wall is studied and correlated with estimates of the shell’s visco-elastic constants. Open questions arising from this comparison are briefly discussed.
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| 8. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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Assessment of ultrasound-induced fracture of polymer-shelled ultrasound contrast agents using superharmonic technique
- 2012
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Konferensbidrag (refereegranskat)abstract
- Ultrasound imaging techniques can be greatly improved by the use of ultrasound contrast agents. Knowledge of the peak negative pressure at which contrast agents fracture is paramount for the imaging application as well as for local drug delivery. Gasholdning microbubbles encapsulated into biocompatible poly vinyl alcohol shells are of particular interest for their enhanced shelf life and demonstratedchemical versatility. A gas core allows microbubbles to efficiently scatter ultrasound waves. In vitro ultrasound tests showed a sufficient enhancement of the backscattered power (25±1 dB), comparable to the soft tissue attenuation coefficients (0.8±0.04 dB/cm MHz) and phase velocities (1519±2 m/s). At temperature values between 24 and 37 °C the monotonic increase of the attenuation and phase velocity with frequency indicates that thick-shelled microbubbles do not resonate in a typical medical ultrasound frequency range of 1-15 MHz. In fact, they work as an amplifier of the incident acoustic wave. The novel approach based on detection of superharmonics (3f and 4f) is proposed for assessment of the fracture pressure threshold, Pthr. In vitro tests suggests that fatigue, i.e. accumulation of damage within the shell, is the major physical mechanism responsible for the fracturing process. It has been observed that there is a decrease of Pthr from 1.15±0.09 MPa to 0.9±0.05 MPa when the number of cycles in the pulse, N, increases from 6 to 12. It is worth noting that the reported pressure values are within clinically approved safety limits. The main conclusion to be drawn from our study is that superharmonic approach appears to be more sensitive in Pthr assessment than traditional second harmonic imaging. This claim is supported also by images acquired with a commercially available system, where contrast pulse sequencing technique, specific to third harmonic, is required for visualization of thick-shelled microbubbles.
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| 9. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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Characterization of Acoustic Properties of PVA-Shelled Ultrasound Contrast Agents
- 2010
-
Ingår i: Ultrasound Contrast Agents. - Italia : Springer-Verlag. - 9788847014930 ; , s. 99-108
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- This work examines the acoustic behavior of ultrasound contrast agents made of poly (vinyl alcohol) (PVA) shelled microbubbles manufactured at three different pH and temperature conditions. Backscattering amplitude, attenuation coefficient and phase velocity of ultrasonic waves propagating through suspensions of PVA contrast agents were measured at temperature values ranging between 24 oC and 37 oC in a frequency range from 3 MHz to 13 MHz. A significant enhancement of the backscattering amplitude and displaying a weak dependence on temperature were observed. Attenuation and phase velocity, on the other hand, showed higher sensitivity to temperature variations. The dependence on system parameters such as the number of cycles, frequency, and exposure of the peak negative pressure, Pthr, at which ultrasound contrast agents fracture was also investigated. The effects of temperature, blood, and, wherever data are available, of the dimension of the microbubbles on Pthr are also considered. The large shell thickness notwithstanding, the results of this investigation show that at room temperature PVA contrast agents fracture at negative peak pressure values within the recommended safety limit. Furthermore, Pthr decreases with increasing temperature, radius of the microbubbles, and number of cycles of the incident wave. In conclusion, these results suggest that PVA-shelled microbubbles may offer a potentially viable system to be employed for both imaging and therapeutic purposes.
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| 10. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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Characterization of acoustic properties of PVA-shelled ultrasound contrast agents : linear properties (Part I)
- 2009
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Ingår i: Ultrasound in Medicine and Biology. - : Elsevier BV. - 0301-5629 .- 1879-291X. ; 35:7, s. 1127-1138
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Tidskriftsartikel (refereegranskat)abstract
- This work examines the linear acoustic behavior of ultrasound contrast agents made of three types of poly (vinyl alcohol) (PVA) shelled microbubbles manufactured at different pH and temperature conditions. Back-scattered power, attenuation coefficient and phase velocity of ultrasonic waves propagating through suspensions of PVA contrast agents were measured at temperature values ranging between 24 degrees C and 37 degrees C in a frequency range from 3 MHz to 13 MHz. Enhancement of the backscattered power higher than 20 dB and displaying a weak dependence on temperature was observed. Attenuation and phase velocity, on the other hand, showed higher sensitivity to temperature variations. A modified version of the Church model, which accounts for the dispersion of the dynamic modulus of the PVA shells, was developed to simultaneously fit the attenuation and phase velocity data at 24 degrees C. The frequency dependence of the storage modulus was found to be that of semiflexible polymeric networks. On the other hand, the frequency dependence of the dynamic loss modulus suggests that additional mechanisms, which may be related to the finite dimensions of the shell and/or to its inhomogeneity, may play a significant role in the dissipation of the acoustic energy. For the microbubbles of interest, this model predicts frequency dependent resonance frequency higher than 100 MHz.
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| 11. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
-
Characterization of acoustic properties of PVA-shelled ultrasound contrast agents : ultrasound-induced fracture (Part II)
- 2009
-
Ingår i: Ultrasound in Medicine and Biology. - : Elsevier BV. - 0301-5629 .- 1879-291X. ; 35:7, s. 1139-1147
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge of the magnitude of the peak negative pressure, P-thr, at which ultrasound contrast agents fracture is relevant for using these microbubbles both as devices for contrast enhancement purposes, as well as carriers of drugs to be delivered locally. In the second part of this communication, the acoustic properties of three types of microbubbles stabilized by poly (vinyl alcohol) (PVA) shells are further investigated. In particular, the dependence of P-thr on system parameters such as the number of cycles, frequency and exposure is examined. The effects of temperature, blood and, wherever data are available, of the dimension of the microbubbles on P-thr are also considered. The large shelf thickness notwithstanding, the results of this investigation show that at room temperature, PVA contrast agents fracture at negative peak pressure values within the recommended safety limit. Furthermore, P-thr decreases with increasing temperature, radius of the microbubbles and number of cycles of the incident wave. Fatigue seems to be a physical mechanism playing a dominant role in the fracture process. The effect of blood on P-thr varies according to condition under which the microbubbles have been synthesized, although stiffening of the shell is observed in most cases. In conclusion, these results suggest that PVA-shelled microbubbles may offer a potentially viable system to be employed for both imaging and therapeutic purposes.
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| 12. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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In vitro contrast-enhanced ultrasound measurements of capillary microcirculation : Comparison between polymer- and phospholipid-shelled microbubbles
- 2011
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Ingår i: Ultrasonics. - : Elsevier BV. - 0041-624X .- 1874-9968. ; 51:1, s. 40-48
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Tidskriftsartikel (refereegranskat)abstract
- The focus of contrast-enhanced ultrasound research has developed beyond visualizing the blood pool and its flow to new areas such as perfusion imaging, drug and gene therapy, and targeted imaging. In this work comparison between the application of polymer- and phospholipid-shelled ultrasound contrast agents (UCAs) for characterization of the capillary microcirculation is reported. All experiments are carried out using a microtube as a vessel phantom. The first set of experiments evaluates the optimal concentration level where backscattered signal from microbubbles depends on concentration linearly. For the polymer-shelled UCAs the optimal concentration level is reached at a value of about 2 x 10(4) MB/ml, whereas for the phospholipid-shelled UCAs the optimal level is found at about 1 x 10(5) MB/ml.Despite the fact that the polymer shell occupies 30% of the radius of microbubble, compared to 0.2% of the phospholipid-shelled bubble, approximately 5-fold lower concentration of the polymer UCA is needed for investigation compared to phospholipid-shelled analogues. In the second set of experiments, destruction/replenishment method with varied time intervals ranging from 2 ms to 3 s between destructive and monitoring pulses is employed. The dependence of the peak-to-peak amplitude of backscattered wave versus pulse interval is fitted with an exponential function of the time gamma = A( 1 - exp(-beta t)) where A represents capillary volume and the time constant beta represents velocity of the flow. Taking into account that backscattered signal is linearly proportional to the microbubble concentration, for both types of the UCAs it is observed that capillary volume is linearly proportional to the concentration of the microbubbles, but the estimation of the flow velocity is not affected by the change of the concentration. Using the single capillary model, for the phospholipid-shelled UCA a delay of about 0.2-0.3 s in evaluation of the perfusion characteristics is found while polymer-shelled UCA provide response immediately. The latter at the concentration lower than 3.6 x 10(5) MB/ml have no statistically significant delay (p < 0.01), do not cause any attenuation of the backscattered signal or saturation of the receiving part of the system. In conclusion, these results suggest that the novel polymer-shelled microbubbles have a potential to be used for perfusion evaluation.
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| 13. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
-
On comparison between polymer- and phospholipid-shelled microbubbles for contrast-enhanced ultrasound measurements of capillary microcirculation.
- 2011
-
Ingår i: Proceedings of the 34<sup>th</sup> Scandinavian Symposium on Physical Acoustics.
-
Konferensbidrag (refereegranskat)abstract
- The focus of contrast-enhanced ultrasound research has developed beyond visualizing the blood circulation to new areas such as perfusion and molecular imaging, drug and gene therapy. This work compares the application of polymer- and phospholipid-shelled ultrasound contrast agents (UCAs) employed for characterization of the capillary microcirculation. To quantify microcirculation destruction/replenishment technique with varied time intervals between destructive and monitoring pulses is used. The dependence of the peak-to-peak amplitude of backscattered wave versus pulse interval is fitted with an exponential function of the time y=A(1-exp(-βt)) , where A represents capillary volume and the time constant β represents velocity of the flow. Working under assumption that backscattered signal is linearly proportional to the microbubble concentration, for both types of the UCAs it is observed that capillary volume, A, is in linearly relationship with the concentration, and the flow velocity, β, remain unchanged. Using 500 µm diameter microtube as a vessel phantom a delay of about 0.25 s in evaluation of the perfusion characteristics is found for the phospholipid-shelled UCA, while polymer-shelled UCA provide response immediately. In conclusion, these results suggest that the novel polymer-shelled microbubbles have a potential to be used for perfusion evaluation.
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| 14. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
-
On the acoustic properties of polymer-shell ultrasonic contrast agents.
- 2008
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Polymer-shelled microbubbles have become the focus of intense research for their enhanced shelf life and demonstrated chemical versatility. These are properties highly sought after in the ultrasonic contrast agents (UCAs) of the next generation, which will be engineered not only to enhance the contrast of ultrasound-based images, but also to function as carriers of drugs to be delivered locally. Here, the results of an experimental investigation of three potentially new UCAs are presented. These microbubbles are stabilized by thick poly (vinyl alcohol) shells. These UCAs differ from each other in their dimensions and shell thickness (order of 0.5 microns). Fundamental to their use as drug carrier is the knowledge of the pressure threshold at which the shell of these UCAs fractures. Therefore, the dependence of this quantity on temperature, number of cycles of the incident pulse, nominal central frequency and pulse repetition frequency of the emitting transducer is examined. The effect of using blood instead of deionized water is also considered. The main conclusion to be drawn from these results is that their thick shell notwithstanding, these microbubbles begin to fracture at values of MI which can be acceptable in clinical applications. This claim is supported also by images acquired by means of commercially available imaging systems. Finally, these values of the pressure threshold are correlated with estimates of the shells’ visco-elastic constants obtained by fitting Church’s model to the frequency-dependent attenuation coefficient and phase velocity. Open questions arising from this comparison are briefly discussed.
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| 15. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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Ultrasound contrast agent loaded with nitric oxide as a theranostic microdevice : Theranostic contrast agent loaded with nitric oxide
- 2015
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Ingår i: Drug Design, Development and Therapy. - 1177-8881. ; 9, s. 2409-2419
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Tidskriftsartikel (refereegranskat)abstract
- The current study describes novel multifunctional polymer-shelled microbubbles (MBs) loaded with nitric oxide (NO) for integrated therapeutic and diagnostic applications, i.e. theranostics, of myocardial ischemia. We used gas filled MBs with an average diameter of 4 µm stabilized by a biocompatible shell of poly(vinyl)alcohol. In vitro acoustic tests showed a sufficient enhancement of the backscattered power (20 dB) acquired from the MBs suspension. The values of attenuation coefficient (0.8 dB/cm MHz) and phase velocities (1517 m/s) were comparable to those reported for the soft tissue. Moreover, polymer MBs demonstrate increased stability compared to clinically approved contrast agents with fracture threshold of about 900 kPa. In vitro chemiluminescence measurements demonstrated that dry powder of NO-loaded MBs releases its gas content in about 2 hours following an exponential decay profile with an exponential time constant equal 36 min. The application of high power ultrasound pulse (MI=1.2) on the MBs resuspended in saline decreases the exponential time constant from 55 to 4 min in air saturated solution and from 17 to 10 min in degased solution. Thus, ultrasound-triggered release of NO is achieved. Cytotoxicity tests indicate that phagocytosis of the MBs by macrophages starts within 6 to 8 hours. This is suitable time for initial diagnostics, treatment and monitoring of the therapeutic effect using single injection of the proposed multifunctional MBs.
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| 16. |
- Grishenkov, Dmitry, 1983-, et al.
(författare)
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Ultrasound contrast agent loaded with nitric oxide as a theranostic microdevise for myocardial ischemia
- 2013
-
Ingår i: European Heart Journal Cardiovascular Imaging.
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Konferensbidrag (refereegranskat)abstract
- Cardiovascular disease (CVD) accounts for 1/3 of total global deaths worldwide. The most widespread CVD is ischemic heart disease. It is the leading cause of death in both genders, equally diagnosed in developed and developing countries with mortality exponentially increasing with age. Efforts of healthcare system should be primary focused on prevention, timely detection, efficient differentiation and instant treatment of the disease.
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| 17. |
- Härmark, Johan, et al.
(författare)
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Investigation of the elimination process of a multimodal polymer-shelled contrast agent in rats using ultrasound and transmission electron microscopy
- 2015
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Ingår i: Biomedical Spectroscopy and Imaging. - 2212-8794. ; 4:1, s. 81-93
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A novel polymer-shelled contrast agent (CA) with multimodal imaging and target specific potential was developed recently and tested for its acoustical properties using different in-vitro setups.OBJECTIVE: The aim of this study was to investigate the elimination of three types of the novel polymer-shelled CA, one unmodified and two shell modified versions, in rats.METHODS: The blood elimination time was estimated by measuring the image intensity, from ultrasound images of the common carotid artery, over time after a bolus injection of the three types of the novel CA. The commercially available CA SonoVue was used as a reference. The subcellular localization of the three CAs was investigated using transmission electron microscopy.RESULTS: The ultrasound measurements indicated a blood half-life of 17–85 s for the different types of the novel CA, which was significant longer than the blood half-life time for SonoVue. Additionally, CAs were exclusively found in the circulatory system, either taken up by, or found in the vicinity of macrophages.CONCLUSIONS: Compared to the commercially available CA SonoVue, the blood circulation times for the three types of the novel polymer-shelled CA were prolonged. Moreover, macrophages were suggested to be responsible for the elimination of the CA.
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| 18. |
- Kothapalli, Satya V. V. N., 1985-, et al.
(författare)
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Dynamic and Structural Behavior of Magnetic PVA-Shelled Microbubbles : Acoustic Characterization
- 2013
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Ingår i: IEEE International Ultrasonics Symposium. - 9781467356862 ; , s. 1509-1512
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Konferensbidrag (refereegranskat)abstract
- Combination of superparamagnetic iron oxide nanoparticles (SPOINs) and the polymer-shelled microbubble (MB) are proposed to be a contrast agent for both magnetic resonance and ultrasound imaging. The introduction of nanoparticles into MBs changes the material properties of encapsulating shell, which further influences on MBs performance as an ultrasound contrast agent. Magnetic MBs were prepared in two following strategies: 1. SPIONs were attached on the surface of MBs (Type A) and 2. SPIONs were physically entrapped in the MBs shell during the initial formation of PVA shell (Type B). A modified Church model was used to fit the attenuation coefficient spectra acquired experimentally. This allowed to recalculate the viscoelastic properties, i.e. storage and loss modulus, and dynamical properties, i.e. resonance frequency and damping coefficient of two types of magnetic MBs. The cross-correlation analysis of the time-domain response from the MBs suspension was used to identify pressure threshold at which MBs shell fractures. Higher values of both viscoelastic and dynamic characteristic were identified for MBs Type B. The estimated total damping ratio above 1 suggested that the MBs Type B behave as an overdamped harmonic oscillator whereas MBs Type A with total damping ratio below 1 possess underdamped harmonic oscillator nature. The predicted resonance frequencies are approximately 13 and 27 MHz for MBs Type A and B respectively. Moreover, the fracture pressure threshold measurements revealed that, higher peak negative pressure is required to fracture MBs Type B than Type A. When the driving pulse consists of 12 cycles, pressure threshold was 1.1 MPa and 1.3 MPa for MBs Type A and B respectively. In conclusion, MBs with nanoparticles loaded on the surface (Type A) appear to be more acoustically active, demonstrate lower resonance frequency, damping and fracture pressure threshold, than MBs with nanoparticles incorporated in the shell (Type B).
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| 19. |
- Kothapalli, Satya V. V. N., et al.
(författare)
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Investigation of polymer-shelled microbubble motions in acoustophoresis
- 2016
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Ingår i: Ultrasonics. - : Elsevier. - 0041-624X .- 1874-9968. ; 70, s. 275-283
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this paper is to explore the trajectory motion of microsize (typically smaller than a red blood cell) encapsulated polymer-shelled gas bubbles propelled by radiation force in an acoustic standing-wave field and to compare the corresponding movements of solid polymer microbeads. The experimental setup consists of a microfluidic chip coupled to a piezoelectric crystal (PZT) with a resonance frequency of about 2.8 MHz. The microfluidic channel consists of a rectangular chamber with a width, w, corresponding to one wavelength of the ultrasound standing wave. It creates one full wave ultrasound of a standing-wave pattern with two pressure nodes at w/4 and 3w/4 and three antinodes at 0, w/2, and w. The peak-to-peak amplitude of the electrical potential over the PZT was varied between 1 and 10 V. The study is limited to no-flow condition. From Gor'kov's potential equation, the acoustic contrast factor, Phi, for the polymer-shelled microbubbles was calculated to about -60.7. Experimental results demonstrate that the polymer-shelled microbubbles are translated and accumulated at the pressure antinode planes. This trajectory motion of polymer-shelled microbubbles toward the pressure antinode plane is similar to what has been described for other acoustic contrast particles with a negative Phi. First, primary radiation forces dragged the polymer-shelled microbubbles into proximity with each other at the pressure antinode planes. Then, primary and secondary radiation forces caused them to quickly aggregate at different spots along the channel. The relocation time for polymer-shelled microbubbles was 40 times shorter than that for polymer microbeads, and in contrast to polymer microbeads, the polymer-shelled microbubbles were actuated even at driving voltages (proportional to radiation forces) as low as 1 V. In short, the polymer-shelled microbubbles demonstrate the behavior attributed to the negative acoustic contrast factor particles and thus can be trapped at the antinode plane and thereby separated from particles having a positive acoustic contrast factor, such as for example solid particles and cells. This phenomenon could be utilized in exploring future applications, such as bioassay, bioaffinity, and cell interaction studies in vitro in a well-controlled environment.
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| 20. |
- Kothapalli, Satya V.V.N. 1985-, et al.
(författare)
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Investigation of Polymer-Shelled Microbubble Motions in Acoustophoresis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The objective of this paper is to explore the trajectory motion of microsize (typically smaller than a redblood cell) encapsulated polymer-shelled gas bubbles propelled by radiation force in an acousticstanding-wave field and to compare the corresponding movements of solid polymer microbeads. Theexperimental setup consists of a microfluidic chip coupled to a piezoelectric crystal (PZT) with aresonance frequency of about 2.8 MHz. The microfluidic channel consists of a rectangular chamberwith a width, w, corresponding to one wavelength of the ultrasound standing wave. It creates one fullwave ultrasound of a standing-wave pattern with two pressure nodes at4w and43w and threeantinodes at 0,2w , and w. The peak-to-peak amplitude of the electrical potential over the PZT wasvaried between 1 and 10 volts. From Gor’kov’s potential equation, the acoustic contrast factor, Φ, forthe polymer-shelled microbubbles was calculated to about -60.7. Experimental results demonstratethat the polymer-shelled microbubbles are translated and accumulated at the pressure antinode planes.This trajectory motion of polymer-shelled microbubbles toward the pressure antinode plane is similarto what has been described for other acoustic contrast particles with a negative Φ. First, primaryradiation forces dragged the polymer-shelled microbubbles into proximity with each other at thepressure antinode planes. Then, secondary radiation forces caused them to aggregate at different spotsalong the channel. The relocation time for polymer-shelled microbubbles was 40 times shorter thanthat for polymer microbeads, and in contrast to polymer microbeads, the polymer-shelledmicrobubbles were actuated even at driving voltages (proportional to radiation forces) as low as 1 volt.In short, the polymer-shelled microbubbles demonstrate the behavior attributed to the negativeacoustic contrast factor particles and thus can be trapped at the antinode plane and thereby seperatedfrom solid particles, such as cells. This phenomenon could be utilized in exploring future applications,such as bioassay, bioaffinity, and cell interaction studies in vitro in a well-controlled environment.
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| 21. |
- Kothapalli, Veeravenkata S., et al.
(författare)
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Assessment of the Viscoelastic and Oscillation Properties of a Nano-engineered Multimodality Contrast Agent
- 2014
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Ingår i: Ultrasound in Medicine and Biology. - : Elsevier BV. - 0301-5629 .- 1879-291X. ; 40:10, s. 2476-2487
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Tidskriftsartikel (refereegranskat)abstract
- Combinations of microbubbles (MBs) and superparamagnetic iron oxide nanoparticles (SPIONs) are used to fabricate dual contrast agents for ultrasound and MRI. This study examines the viscoelastic and oscillation characteristics of two MB types that are manufactured with SPIONs and either anchored chemically on the surface (MBs-chem) or physically embedded (MBs-phys) into a polymer shell. A linearized Church model was employed to simultaneously fit attenuation coefficients and phase velocity spectra that were acquired experimentally. The model predicted lower viscoelastic modulus values, undamped resonance frequencies and total damping ratios for MBs-chem. MBs-chem had a resonance frequency of approximately 13 MHz and a damping ratio of approximately 0.9; thus, MBs-chem can potentially be used as a conventional ultrasound contrast agent with the combined functionality of MRI detection. In contrast, MBs-phys had a resonance frequency and damping of 28 MHz and 1.2, respectively, and requires further modification of clinically available contrast pulse sequences to be visualized.
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| 22. |
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| 23. |
- Kothapalli, Veera Venkata Satya Naray, 1985-, et al.
(författare)
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Coded Excitation Technique in Detection of Polymeric-Shelled Ultrasound contrast Agents: in Vitro Study
- 2011
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Ingår i: 8th International Conference on Nanosciences & Nanotechnologies (NN11) 12-15 July 2011, Thessaloniki, Greece..
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Konferensbidrag (refereegranskat)abstract
- A novel ultrasound contrast agent (UCA) based on air-filled polymer-shelled microbubbles, is prepared within 3MiCRON project for multimodality approach covering ultrasound, MRI and SPECT investigation. These bubbles have thick, about 30% of the radius, shell providing greater stability and longer half life in a pulmonary circulation compare to commercially available phospholipid UCAs. In addition, extensive storage capacity and possibility to incorporate drugs or pharmacological relevant materials are inherited to these bubbles. Understanding the behavior of the UCA under ultrasound exposure is paramount to the proper and total exploitation of all unique features that these gas-filled microdevice offers. Even though, thickness of the polymeric shell is considerably higher than of commercial UCAs, the enhancement of backscattered power of about 25 dB produced from suspension insonified at low pressure (100 kPa) was observed. It should be noted that thick polymer shell could still be disrupted by high pressure (1 MPa) ultrasonic pulse. Nevertheless, diagnostic imaging typically utilizes the intermediate pressure level, where nonlinear oscillation of the microbubbles give rise to harmonic component in the received echo. It was observed that at pressure level of 400 kPa, Pulse Inversion (PI) technique fail to distinguish between the regions filled with polymer UCA and surrounding ultrasound phantom, mimicking liver tissue. In this paper, a coded excitation technique is proposed to characterize the non-linear properties of the polymer-shelled microbubbles in vitro at intermediate pressure. For a decade ago, coded excitation technique has been adopted into the ultrasound scanners in order to increase the signal-to-noise ratio (SNR) and penetration depth, while matching filters compensates the decrease in axial resolution. In the proposed method, a time domain signal is modulated by a several window functions (e.g. Blackman-Harries, Hanning, Hamming, and Kaiser-Bessel) with or without linear chirp pulses constructed for experiments in vitro. Our preliminary results suggest that coded excitation technique offers an increase of approximately 15dB in contrast-to-tissue ration (CTR) compared to the result achieved from a commercially available Pulse Inversion technique. In conclusion, proposed polymer-shelled microbubbles provide a viable system to be used among the next generation of UCAs, and in combination with improved signal handling is superior not only in image enhancement relevant to diagnostics but also in localized and specific drug delivery for non-invasive therapy.
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| 24. |
- Kothapalli, Veera Venkata Satya Naray, 1985-, et al.
(författare)
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Unique pumping-out fracturing mechanism of a polymer-shelled contrast agent : An acoustic characterization and optical visualization
- 2014
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Ingår i: IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control. - 0885-3010 .- 1525-8955. ; 62:3, s. 451-462
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Tidskriftsartikel (refereegranskat)abstract
- This work describes the fracturing mechanism of air-filled microbubbles (MBs) encapsulated by a cross-linked poly(vinyl alcohol) (PVA) shell. The radial oscillation and fracturing events following the ultrasound exposure were visualized with an ultrahigh-speed camera, and backscattered timedomain signals were acquired with the acoustic setup specific for harmonic detection. No evidence of gas emerging from defects in the shell with the arrival of the first insonation burst was found. In optical recordings, more than one shell defect was noted, and the gas core was drained without any sign of air extrusion when several consecutive bursts of 1 MPa amplitude were applied. In acoustic tests, the backscattered peak-to-peak voltage gradually reached its maximum and exponentially decreased when the PVA-based MB suspension was exposed to approximately 20 consecutive bursts arriving at pulse repetition frequencies of 100 and 500 Hz. Taking into account that the PVA shell is porous and possibly contains large air pockets between the cross-linked PVA chains, the aforementioned acoustic behavior might be attributed to pumping gas from these pockets in combination with gas release from the core through shell defects. We refer to this fracturing mechanism as pumping-out behavior, and this behavior could have potential use for the local delivery of therapeutic gases, such as nitric oxide.
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| 25. |
- Larsson, Malin K., et al.
(författare)
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Endocardial border delineation capability of a multimodal polymer-shelled contrast agent
- 2014
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundA novel polymer-shelled contrast agent (CA) with high mechanical and chemical stability was recently developed [1]. In excess to its ultrasound properties, it also supports targeted and multimodal imaging [2-4]. Even though these new possibilities have the potential to lead to new methodologies and approaches for non-invasive diagnosis, it is important that the fundamental diagnostic features in contrast-enhanced ultrasound are preserved. The aim of this study was therefore to examine the clinical use of the polymer-shelled CA by analyzing the left ventricular endocardial border delineation capability in a porcine model. In addition, physiological effects due to CA injections were studied.MethodsThe endocardial border delineation capability was assessed in a comparative study, which included three doses (1.5 ml, 3 ml and 5 ml, [5x108 MBs/ml]) of the polymer-shelled CA and the commercially available CA SonoVue® (1.5 ml, [2-5x108 MBs/ml]). Ultrasound images of the left ventricle were evaluated manually by blinded observers (n=3) according to a 6-segment model, in which each segment was graded as 0=not visible, 1=barely visible or 2=well visible, as well as semi-automatically by a segmentation software. Furthermore, duration of clinically useful contrast enhancement and changes in physiological parameters were evaluated.ResultsFor the highest dose of the polymer-shelled CA, the obtained segment scores, time for clinically sufficient contrast enhancement and semi-automatic delineation capability were comparable to SonoVue®. Moreover, neither dose of the polymer-shelled CA did affect the physiological parameters.ConclusionThis study demonstrated that the polymer-shelled CA can be used in contrast-enhanced diagnostic imaging without influence on major physiological parameters.
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| 26. |
- Larsson, Malin K., et al.
(författare)
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Endocardial border delineation capability of a novel multimodal polymer-shelled contrast agent
- 2014
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Ingår i: Cardiovascular Ultrasound. - : Springer Science and Business Media LLC. - 1476-7120. ; 12, s. 24-
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Tidskriftsartikel (refereegranskat)abstract
- Background: A novel polymer-shelled contrast agent (CA) with multimodal and target-specific potential was developed recently. To determine its ultrasonic diagnostic features, we evaluated the endocardial border delineation as visualized in a porcine model and the concomitant effect on physiological variables. Methods: Three doses of the novel polymer-shelled CA (1.5 ml, 3 ml, and 5 ml [5 x 10(8) microbubbles (MBs)/ml]) and the commercially available CA SonoVue (1.5 ml [2-5 x 10(8) MBs/ml]) were used. Visual evaluations of ultrasound images of the left ventricle were independently performed by three observers who graded each segment in a 6-segment model as either 0 = not visible, 1 = weakly visible, or 2 = visible. Moreover, the duration of clinically useful contrast enhancement and the left ventricular opacification were determined. During anesthesia, oxygen saturation, heart rate, and arterial pressure were sampled every minute and the effect of injection of CA on these physiological variables was evaluated. Results: The highest dose of the polymer-shelled CA gave results comparable to SonoVue. Thus, no significant difference in the overall segment score distribution (2-47-95 vs. 1-39-104), time for clinically sufficient contrast enhancement (20-40 s for both) and left ventricular overall opacification was found. In contrast, when comparing the endocardial border delineation capacity for different regions SonoVue showed significantly higher segment scores for base and mid, except for the mid region when injecting 1.5 ml of the polymer-shelled CA. Neither high nor low doses of the polymer-shelled CA significantly affected the investigated physiological variables. Conclusions: This study demonstrated that the novel polymer-shelled CA can be used in contrast-enhanced diagnostic imaging without influence on major physiological variables.
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| 27. |
- Larsson, Malin, et al.
(författare)
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Visualization of multimodal polymer-shelled contrast agents using ultrasound contrast sequences : an experimental study in a tissue mimicking flow phantom
- 2013
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Ingår i: Cardiovascular Ultrasound. - : Springer Science and Business Media LLC. - 1476-7120. ; 11, s. 33-
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Tidskriftsartikel (refereegranskat)abstract
- Background: A multimodal polymer-shelled contrast agent (CA) with target specific potential was recently developed and tested for its acoustic properties in a single element transducer setup. Since the developed polymeric CA has different chemical composition than the commercially available CAs, there is an interest to study its acoustic response when using clinical ultrasound systems. The aim of this study was therefore to investigate the acoustic response by studying the visualization capability and shadowing effect of three polymer-shelled CAs when using optimized sequences for contrast imaging. Methods: The acoustic response of three types of the multimodal CA was evaluated in a tissue mimicking flow phantom setup by measuring contrast to tissue ratio (CTR) and acoustic shadowing using five image sequences optimized for contrast imaging. The measurements were performed over a mechanical index (MI) range of 0.2-1.2 at three CA concentrations (10(6), 10(5), 10(4) microbubbles/ml). Results: The CTR-values were found to vary with the applied contrast sequence, MI and CA. The highest CTR-values were obtained when a contrast sequence optimized for higher MI imaging was used. At a CA concentration of 106 microbubbles/ml, acoustic shadowing was observed for all contrast sequences and CAs. Conclusions: The CAs showed the potential to enhance ultrasound images generated by available contrast sequences. A CA concentration of 106 MBs/ml implies a non-linear relation between MB concentration and image intensity.
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| 28. |
- Loskutova, Ksenia
(författare)
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Perfluorocarbon microdroplets stabilized by cellulose nanofibers : Toward ultrasound-mediated diagnostics and therapy
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ultrasound contrast agents consist of gas-filled micrometer-sized bubbles that are injectedinto the blood stream. Ultrasound contrast agents are an invaluable tool for ultrasound imaging of the cardiac muscle and highly vascularized structures such as kidneys and the liver. The ability of gas-filled microbubbles to enhance contrast in ultrasound imaging comes from their increased scattering ability due to significantly lower compressibility compared to surrounding soft tissues.The discovery of acoustic droplet vaporization, the phase-transition of liquid-filleddroplets into gas-filled microbubbles upon ultrasound exposure, has expanded the potential utility of ultrasound-mediated diagnostics and therapy to include applications such as gas embolization, histotripsy, and localized drug delivery. Multiple requirements are put onto both gas-filled microbubbles and phase-change contrast agents: they have to be non-toxic, acoustically active at clinically relevant pressure amplitudes, and their dynamic behavior has to be predictable to maximize the therapeutic or diagnostic effect while minimizing mechanical damage to surrounding healthy tissue. Novel designs of phase-change contrast agents that are able to undergo acoustic droplet vaporization could enable improved in vivo stability compared to conventional gas-filled ultrasound contrast agents.Pickering emulsions, with solid particles used as stabilizing agents instead of surfactants, have an increased stability compared to conventional emulsions. Cellulose-based Pickering emulsions in particular have previously been investigated for biomedical applications. Cellulose is a suitable material in biomedical applications as it originates from renewable sources, is biocompatible, and the surface can be easily modified. To the author’s current knowledge, cellulose-based Pickering emulsions have not previously been investigated for ultrasound-mediated applications. It is necessary to know the mechanical and acoustic properties of novel formulations and their impact on biological cells for their translation into in vivo research and future clinical use.In this thesis, the acoustic, mechanical, and biological properties of cellulose nanofiber(CNF)-shelled perfluoropentane (PFP) droplets, a type of Pickering emulsion, were investigated for ultrasound-mediated medical applications. Firstly, the current state-of-the-art and development of phase-change contrast agents, the mechanism behind acoustic droplet vaporization, and potential ultrasound-mediated medical applications were investigated. Secondly, a theoretical model that would describe and predict the acoustic response of CNF-shelled PFP droplets undergoing acoustic droplet vaporization was developed. Thirdly, the compressibility of CNF-shelled PFP droplets using an acoustophoretic setup was measured. Later, the effect of the geometry of the surrounding medium and acoustic parameters on the acoustic response of CNF-shelled PFP droplets was explored. Finally, the biocompatibility of CNF-shelled PFP droplets cells was investigated through a hemolysis assay and measurement of change in cell viability of breast cancer cells.The CNF shell has a significant impact on the predicted resonance behavior and compressibility of CNF-shelled PFP droplets, as it has significantly larger bulk and Young’s modulus than previously reported shell materials. The predicted linear resonance behavior was in the upper range of medical ultrasound (5-8 MHz), making harmonic imaging at optimal conditions difficult. However, it was demonstrated that CNF-shelled PFP droplets could be imaged using a nonlinear ultrasound imaging sequence at a frequency regularly used in clinics. Thus, CNF-shelled PFP droplets were able to undergo acoustic droplet vaporization at clinically relevant conditions. The peak negative pressure of the incident acoustic wave had a significant impact on the acoustic response of CNF-shelled PFP droplets, as higher acoustic pressure amplitudes resulted in a more disruptive behavior. Finally, CNF-shelled PFP droplets did not influence the cell viability of breast cancer cells. This was true regardless of whether or not a non-encapsulated cytotoxic drug with a known impact on cell viability was present. In summary, the results of this work showed that CNF-shelled PFP droplets are biocompatible and acoustically active at clinically relevant conditions, which shows that cellulose-based Pickering emulsions have potential in ultrasound-mediated diagnostics and therapy.
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| 29. |
- Poehlman, Melanie, et al.
(författare)
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Magnetic microbubbles for multimodality imaging : the importance of the shell structure for low and high frequency mechanics
- 2013
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Konferensbidrag (refereegranskat)abstract
- There is a growing interest in magnetic microbubbles (MBs) for simultaneous enhanced ultrasound (US) and enhanced magnetic resonance imaging (MRI) to support well-established imaging procedures as well as new emerging diagnostic and therapeutic applications. However, the development of hybrid contrast agents is challenging, because their design needs to satisfy a variety of requirements such as a sufficient stability of the probe for the circulation within the cardiovascular system, the production of an adequate US echo signal and a reasonable reduced relaxation time of nearby located protons. The studied magnetic MBs consist of an air-filled core, which is encapsulated by a soft hydrogel-like shell composed of poly(vinyl alcohol) and superparamagnetic iron oxide nanoparticles (SPIONs)[1]. Two strategies were used to combine magnetic nanoparticles with the polymeric shell: SPIONs were either covalently attached to the shell surface via a post-chemical treatment or embedded physically inside the shell during the MBs’ synthesis. In particular, we were interested on the impact of the used SPIONs integration strategy on low and high frequency mechanics of the magnetic MBs. Therefore, we used a straightforward characterization of the MBs on the single particle level to correlate the synthesis with the MBs’ morphological properties and low frequency mechanics that were studied in quasi-static force measurements with atomic force microscopy. High frequency mechanics were investigated by exposure of an ensemble of MBs to an acoustic field. By further correlation of low and high frequency mechanics, we were able to bridge the gap between synthesis and the MBs macroscopic properties relevant for their application. The shown approach offers the possibility to sustainable design and optimize complex probes based on an improved understanding of structure/property relations.
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| 30. |
- Poehlmann, Melanie, et al.
(författare)
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On the interplay of shell structure with low- and high-frequency mechanics of multifunctional magnetic microbubbles
- 2014
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Ingår i: Soft Matter. - : Royal Society of Chemistry (RSC). - 1744-683X .- 1744-6848. ; 10:1, s. 214-226
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Tidskriftsartikel (refereegranskat)abstract
- Polymer-shelled magnetic microbubbles have great potential as hybrid contrast agents for ultrasound and magnetic resonance imaging. In this work, we studied US/MRI contrast agents based on air-filled poly(vinyl alcohol)-shelled microbubbles combined with superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs are integrated either physically or chemically into the polymeric shell of the microbubbles (MBs). As a result, two different designs of a hybrid contrast agent are obtained. With the physical approach, SPIONs are embedded inside the polymeric shell and with the chemical approach SPIONs are covalently linked to the shell surface. The structural design of hybrid probes is important, because it strongly determines the contrast agent's response in the considered imaging methods. In particular, we were interested how structural differences affect the shell's mechanical properties, which play a key role for the MBs' US imaging performance. Therefore, we thoroughly characterized the MBs' geometric features and investigated low-frequency mechanics by using atomic force microscopy (AFM) and high-frequency mechanics by using acoustic tests. Thus, we were able to quantify the impact of the used SPIONs integration method on the shell's elastic modulus, shear modulus and shear viscosity. In summary, the suggested approach contributes to an improved understanding of structure-property relations in US-active hybrid contrast agents and thus provides the basis for their sustainable development and optimization.
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