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  • 1. Brismar, Torkel B.
    et al.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Gustafsson, Björn
    Härmark, Johan
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.
    Barrefelt, Åsa
    Kothapalli, Satya V. V. N.
    KTH, School of Technology and Health (STH), Medical Engineering, Neuronic Engineering.
    Margheritelli, Silvia
    Oddo, Letizia
    Caidahl, Kenneth
    Hebert, Hans
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.
    Paradossi, Gaio
    Magnetite Nanoparticles Can Be Coupled to Microbubbles to Support Multimodal Imaging2012In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 13, no 5, p. 1390-1399Article in journal (Refereed)
    Abstract [en]

    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.

  • 2. Capece, Sabrina
    et al.
    Chiessi, Ester
    Cavalli, Roberta
    Giustetto, Pierangela
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Paradossi, Gaio
    A general strategy for obtaining biodegradable polymer shelled microbubbles as theranostic devices2013In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 49, no 51, p. 5763-5765Article in journal (Refereed)
    Abstract [en]

    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.

  • 3. Capese, Sabrina
    et al.
    Chiessi, E.
    Cavalli, R.
    Giustetto, P.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Paradossi, Gaio
    Diapartimento di Chimica, Università di Roma Tor Vergata.
    A general strategy for the obtainment of biodegradable polymer shelled microbubbles as theranostic device2013Conference paper (Refereed)
    Abstract [en]

    Introduction

    Fabrication 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.

    Methods

    Deposition 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.

    Results

    Lipid 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.

    Conclusions

    This new class of polymer shelled vesicles/microbubbles entails features desired in a potential theranostic microdevice.

  • 4.
    Chen, Hongjian
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Evangelou, Dimitris
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging. Karolinska Institutet (KI), CLINTEC – Division of Medical Imaging and Technology.
    Sequence design for ultrasound imaging of polyvinyl alcohol microbubbles2019Conference paper (Refereed)
    Abstract [en]

    Nonlinear behavior of the ultrasound contrast agent (UCA) offers a unique feature to be distinguished from the surrounding tissue. In a recent years several methods were developed to enhance the nonlinear response of UCA. Crucial for efficient differentiation of the nonlinear response of UCA from the surrounding tissue is to design the contrast pulse sequence specific to the unique nonlinear properties that the particular UCA is offering.

    In the previous study, the nonlinear response from a novel polyvinyl alcohol (PVA) microbubbles (MB), in ultra-harmonic region was investigated over a pressure range from 50 kPa to 300 kPa. In this study, five contrast pulse sequences and reference B-mode sequence were designed to visualize PVA MB. The performance of those sequences were evaluated and compared.

  • 5.
    Faridi, M. A.
    et al.
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ramachandraiah, H.
    KTH, School of Biotechnology (BIO).
    Iranmanesh, I. S.
    KTH, School of Biotechnology (BIO). KTH, School of Engineering Sciences (SCI), Applied Physics.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Wiklund, Martin
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Russom, Aman
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Microbubble assisted cell sorting by acoustophoresis2016In: 20th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2016, Chemical and Biological Microsystems Society , 2016, p. 1677-1678Conference paper (Refereed)
    Abstract [en]

    Polymer shelled gas microbubbles (MBs) are used to sort cells in a microfluidic chip under acoustic standing waves (SW). When particles are subjected to SW based on their acoustic contrast factor (ACF) they migrate to nodes (positive contrast factor particles; PACP) or antinodes (negative acoustic contrast particles; NACP)[1]. We have bounded functionalized MBs with cells such that, they can be selectively migrated to antinodes under SW and sorted from unbounded cell both in no flow and flow conditions. Here we demonstrate acoustic mediated microbubble tagged cell sorting with 75% efficiency.

  • 6.
    Faridi, Muhammad Asim
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. mafaridi@kth.se.
    Ramachandraiah, Harisha
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Iranmanesh, Ida Sadat
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Wiklund, Martin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Russom, Aman
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    MicroBubble Activated Acoustic Cell Sorting: BAACSIn: Biomedical microdevices (Print), ISSN 1387-2176, E-ISSN 1572-8781Article in journal (Refereed)
    Abstract [en]

    Acoustophoresis, the ability to acoustically manipulate particles and cells inside a microfluidic channel, is a critical enabling technology for cell-sorting applications. However, one of the major impediments for routine use of acoustophoresis at clinical laboratory has been the reliance on the inherent physical properties of cells for separation. Here, we present a microfluidic-based microBubble-Activated Acoustic Cell Sorting (BAACS) method that rely on the specific binding of target cells to microbubbles conjugated with specific antibodies on their surface for continuous cell separation using ultrasonic standing wave. In acoustophoresis, cells being positive acoustic contrast particles migrate to pressure nodes. On the contrary we show that air-filled polymer-shelled microbubbles being strong negative acoustic contrast particles migrate to pressure antinodes at acoustic pressure amplitudes as low as 60 kPa. As a proof of principle, using the BAACS strategy, we demonstrate the separation of cancer cell line in a suspension with better than 75% efficiency. Moreover, 100% of the microbubble-cell conjugates migrated to the anti-node. Hence a better upstream affinity-capture has the potential to provide higher sorting efficiency. The BAACS technique may potentially provide a simplistic approach for similar sized selective isolation of cells, and is suited for applications in point of care.

  • 7.
    Faridi, Muhammad Asim
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. mafaridi@kth.se.
    Ramachandraiah, Harisha
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Iranmanesh, Ida Sadat
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Wiklund, Martin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Russom, Aman
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    MicroBubble Activated Acoustic Cell Sorting: BAACS2017In: Biomedical microdevices (Print), ISSN 1387-2176, E-ISSN 1572-8781, Vol. 19, no 2, article id 23Article in journal (Refereed)
    Abstract [en]

    Acoustophoresis, the ability to acoustically manipulate particles and cells inside a microfluidic channel, is a critical enabling technology for cell-sorting applications. However, one of the major impediments for routine use of acoustophoresis at clinical laboratory has been the reliance on the inherent physical properties of cells for separation. Here, we present a microfluidic-based microBubble-Activated Acoustic Cell Sorting (BAACS) method that rely on the specific binding of target cells to microbubbles conjugated with specific antibodies on their surface for continuous cell separation using ultrasonic standing wave. In acoustophoresis, cells being positive acoustic contrast particles migrate to pressure nodes. On the contrary we show that air-filled polymer-shelled microbubbles being strong negative acoustic contrast particles migrate to pressure antinodes at acoustic pressure amplitudes as low as 60 kPa. As a proof of principle, using the BAACS strategy, we demonstrate the separation of cancer cell line in a suspension with better than 75% efficiency. Moreover, 100% of the microbubble-cell conjugates migrated to the anti-node. Hence a better upstream affinity-capture has the potential to provide higher sorting efficiency. The BAACS technique may potentially provide a simplistic approach for similar sized selective isolation of cells, and is suited for applications in point of care.

  • 8.
    Ghorbani, Morteza
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Araz, Sheybani Aghdam
    Moein, Talebian
    Ali, Kosar
    Fevzi, Cakmak Cebeci
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Svagan, Anna Justina
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology.
    Facile Hydrodynamic Cavitation ON CHIP via Cellulose Nanofibers Stabilized Perfluorodroplets inside Layer-by-Layer Assembled SLIPS SurfacesIn: Article in journal (Refereed)
  • 9. Ghorbani, Morteza
    et al.
    Chen, Hongjian
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems.
    Villanueva, Luis Guillermo
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Kocsar, Ali
    Intensifying cavitating flows in microfluidic devices with poly(vinyl alcohol) (PVA) microbubbles2018In: Physics of Fluids, Vol. 30, no 10Article in journal (Refereed)
    Abstract [en]

    Cavitation and the energy associated with the collapse of resulting cavitation bubbles constitute an important research subject. The collapse of the hydrodynamic cavitation bubbles at the outlet of the flow elements leads to a high energy release and generates localized shock waves and a large temperature rise on exposed surfaces. The concept of “hydrodynamic cavitation on chip” is an emerging topic which emphasizes phase change phenomena in microscale and their utilizations in energy and biomedical applications. This study is aimed to investigate the potential of poly(vinyl alcohol) (PVA) Microbubbles (MBs) to generate cavitation bubbles and to evaluate their effects on flow regimes and energy dissipation. For this, three different microchannel configurations with different roughness elements were considered. The structural side wall and surface roughened channels were fabricated along with the smooth channel according to the techniques adopted from semiconductor based microfabrication. The upstream pressure varied from 1 to 7 MPa, and the flow patterns were recorded and analyzed using a high-speed camera. The pressure was locally measured at three locations along the microfluidic devices to determine the conditions for fully developed cavitating flows. The results were compared to the pure water case, and different trends for the cavitating flow pattern transitions were obtained for the water-PVA MB solution case. Accordingly, the twin cavity clouds extended to the end of the side wall roughened channel at a lower upstream pressure for the case of PVA MBs, while the smooth and surface roughened channels do not demonstrate this flow pattern. In addition, the cavitation number has the lowest values under the same working conditions for the case of PVA MBs. Moreover, the impact pressure generated by the bubble collapse inside the side wall roughened channel for the case of PVA MBs was notably higher than that for pure water.

  • 10.
    Ghorbani, Morteza
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Olofsson, Karl
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Benjamins, Jan-willem
    Loskutova, Ksenia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Paulraj, Thomas
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology, Polymeric Materials.
    Wiklund, Martin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Svagan, Anna Justina
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology.
    Unravelling the Acoustic and Thermal Responses of Perfluorocarbon Liquid Droplets Stabilized with Cellulose NanofibersIn: Article in journal (Refereed)
  • 11.
    Ghorbani, Morteza
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Svagan, Anna Justina
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology.
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging. KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, Marcus Wallenberg Laboratory MWL. Karolinska Institutet (KI), CLINTEC – Division of Medical Imaging and Technology.
    Acoustic Response of a Novel Class of Pickering Stabilized Perfluorodroplets2019Conference paper (Refereed)
    Abstract [en]

    Introduction

    Acoustic Droplet Vaporization (ADV) is a phase change phenomenon in which the liquid state, in the form of droplets, is converted to gas as a result of bursts in the excited ultrasound field. Having a wide range of medical applications, ADV has drawn considerable attention in imaging [1], diagnosis and critical medical treatment [2]. Therefore, benefitting from its broad potentials, with the consideration of its capability in localized noninvasive energy exposure, it is possible to utilize its effect in different medical applications from targeted drug delivery [3] to embolotherapy [4].

    Apart from the droplet characterization and ADV effectiveness on the applied region, the physics of ADV and particularly the ultrasound analysis is an essential parameter in the initiation of the vaporization. This part, which is related to acoustic wave physics, implies that ADV is mostly dependent on ultrasound pressure, frequency and temperature. In this sense, Miles et al. [5] tried to find incident negative pressure - called as ADV threshold- which is necessary for the induction of nucleation. It was successfully shown that the negative pressure required for the nucleation prior to collapse can be determined via perturbation analysis of a compressible inviscid flow around a droplet for various frequencies and diameters. In addition, the fluid medium which constitutes the droplet emulsion and the surrounding fluid constructs a significant field within ADV. In this regard, there are many studies which illustrated that the diameter of the droplets subjected to the acoustic waves undergoes a significant expansion of 5 to 6 times of their regular sizes [6-8].

    In this study, a new type of pickering stabilized perfluorodroplets (PFC) was examined under the effect of the different acoustic parameters to evaluate its potential in the acoustic droplet vaporization process. To assess the pressure effects on the stabilized droplets, the acoustic power within the ultrasound tests was varied and the phase trasnition was characterized according to the experimental conditions. Opticell® was utilized as the transparent device to visualize the droplets, which were exposed to the acoustic waves with the aid of the microscope and multi-well microplate.

    Methods

    Materials and emulsion preparation

    Perfluoropentane (PFC5) was purchased from Apollo Scientific (City, U.K.). Bleached sulfite pulp (from Nordic Paper Seffle AB, Sweden) was used in the production of the cationic cellulose nanofibers (CNFs). The CNF suspension (1.32 wt%) were prepared as described previously [9]. The CNFs had a dimension of 3.9 ± 0.8 nm in width and a length in the micrometer range. The amount of cationic groups was 0.13 mmol per g fiber, obtained from conductometric titration [9]. A suspension of CNF (0.28 wt%) was prepared by diluting the stock CNF with MilliQ-water (pH of diluted CNF suspension was 9.5). The suspension was treated with ultra-sonication at amplitude of 90% for 180 s (Sonics, Vibracell W750). The suspension was brought to room temperature. An amount of 36 g of the 0.28 wt% CNF suspension was mixed with 1 g of PFC5. The mixture was sonicated for 60s at an amplitude of 80% (under ice-cooling) to obtain the CNF-stabilized PFC5 droplets.

    The protocol for the acoustic tests

    100 μL of CNF-stabilized PFC5 droplets were added to 1900 μL of deionized water in order to prepare the solution which were exposed to the ultrasound waves. The droplet sample, diluted 1:19 in distilled water was introduced to the Opticell® and the acoustic waves at a fixed frequency and different powers were applied to the trageted area inside the Opticell® which is located inside a water bath. The ultrasound triggered sample then was placed under a 20X magnification objective of upright transmitted light microscope (ECLIPSE Ci-S, Nikon, Tokyo, Japan). 

    The acoustic tests were performed using high-power tone burst pulser-receiver (SNAP Mark IV,  Ritec, Inc., Warwick, RI, USA) equipped with a transducer (V382-SU Olympus NDT, Waltham, MA ) operating at the frequency of 3.5 MHz. The emulsion of CNF-stabilized PFC5 droplets were exposed to the power range which has the acsending trend from -30 to 0 dB at the given frequency. To investigate the droplet size variations at each power between, the droplets were collected inside the Opticell® and the droplet diameter was measured with the aid of the ImageJ software (version 1.50b, National institutes of health, USA) to determine the concentration and size distribution. The Gaussian distribution is ploted with mean value and standad deviation recover from the experimental data. An in-house image edge detection MATLAB™ script (MathWorks Inc., Natick, MA) were applied to analyze the images obtained from the microscope and provides the size and volume distributions.

    Results

    The size of PFP droplets is an important parameter to controll in the therapeutic applications. Here, a new type of Pickering stabilized perfluorodroplets were prepared where the PFP/water interface was stabilized with cellulose nanofibers (CNF) and the size of the droplets could easily be controlled by varying the amount of CNF added.  The resulting droplets were investigated using a single crystal transducer. Apart from the medical applications, controlling the droplet size is important from droplet dynamics point of view, becausethe interfacial energy is crucial in the assumption of the critical nucleus radius. Therefore, it is possible to estimate the negative peak pressure required for the phase transition once the droplet is controlled and interfacial energy deposited inside and on the surface of the droplet are balanced.

    According to the results in Figure 1, there is an appreciable rise of the size of the droplets after ultrasound waves exposure, particularly at -8 dB power. The experiments were performed for 30 seconds at different powers ranging from -30 to 0 dB, while the frequency was kept constant at 3.5 MHz, burst width in cycles was selected as 12 and repetition rate was set to 100. Images included in Figure 1 demonstrate major transitions in the intervals at -16, -8 and 0 dB. As shown in this figure, the droplet size increased with the power rise and more bubbles with bigger sizes appears at higher powers. This outcome implies the significant role of the applied frequency and power on the phase shift and subsequent mechanisms as a result of the acoustic wave exposure on the new nontoxic and incompatible droplet type.

    Figure 2 shows the average number of droplets and volume distribution at the corresponding powers to the Figure 1. It is shown that while the average diameter of the droplets is around 3.5 µm, the generated bubbles, as a result of the ADV, reaches up to 15 µm at the highest possible power. For each set of experiment (corresponding to a given power) 32 images were taken, thus, to reduce the errors and obtain the standard deviation (approximately 0.8 for all the cases), the presented diagrams for the droplet distributions exhibits the mean value for all of the acquired images. Therefore, it is shown that the droplet emulsion exhibited in NO US in Figure 2, which shows the regular view and distribution range of the CNF-stabilized PFC5 droplets at the room temperature, experiences ADV process with the diameter rise of about 5 times at the highest power when the frequency is fixed at 3.5 MHz.

    Conclusions

    The results show that there is appreciable rise on the size of the droplets after ultrasound waves exposure at a fixed frequency. Acoustic droplet vaporization (ADV) was illustrated at different powers for CNF-stabilized PFC5 droplets as a new class of pickering stabilized perfluorodroplets with the increase in the size of the droplets and following phase trasition to bubbles. Diameter increase of 5 times were obtained after the ultrasound exposure indicating the efficiency of the suggested droplets for the ADV process and therapeutic applications.   

    References

    [1] Arena CB, Novell A, Sheeran PS, Puett C, Moyer LC, Dayton PA, Dual-Frequency Acoustic Droplet Vaporization Detection for Medical Imaging 2015, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, 62: 9.

    [2] Kripfgans OD, Fowlkes JB, Miller DL, Eldevik OP, Carson PL, Acoustic droplet vaporization for therapeutic and diagnostic applications 2000, Ultrasound Med. Biol, 26:1177–1189.

    [3] Kang ST, Yeh CK, Intracellular Acoustic Droplet Vaporization in a Single Peritoneal Macrophage for Drug Delivery Applications 2011, Langmuir, 27:13183–13188.

    [4] Zhu M, Jiang L, Fabiilli ML, Zhang A, Fowlkes JB, Xu LX, Treatment of murine tumors using acoustic droplet vaporization-enhanced high intensity focused 2013, Ultrasound Phys. Med. Biol, 58:6179–6191.

    [5] Miles CJ, Doering CR, Kripfgans OD, Nucleation pressure threshold in acoustic droplet vaporization 2016, Journal of Applied Physics, 120:034903.

    [6] Sheeran PS, Wong VP, Luois S, McFarland RJ, Ross WD, Feingold S, Matsunaga TO, Dayton PA, Decafluorobutane as a phase-change contrast agent for low-energy extravascular ultrasonic imaging 2011, Ultrasound Med. Biol, 37:1518–1530.

    [7] Kripfgans OD, Fowlkes JB, Miller DL, Eldevik OP, Carson PL, Acoustic droplet vaporization for therapeutic and diagnostic applications 2000, Ultrasound Med. Biol, 26:1177–1189.

    [8] Kang S, Huang Y, Yeh C, Characterization of acoustic droplet vaporization for control of bubble generation under flow conditions 2014, Ultrasound Med. Biol, 40:551–561.

    [9] Svagan AJ, Benjamins JW, Al-Ansari Z, Shalom DB, Müllertz A, Wågberg L, Löbmann K, Solid cellulose nanofiber based foams–towards facile design of sustained drug delivery systems 2016, J. Control Release, 244:74–82 (Part A).

     

  • 12.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institutet (KI), CLINTEC – Division of Medical Imaging and Technology.
    Contrast agent for early diagnostics and monitoring of progression of liver cancer (hepatocellular carcinoma)2013Conference paper (Refereed)
  • 13.
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, MWL Ultrasound. KTH, School of Technology and Health (STH), Medical Engineering.
    Diagnostic Power of Different Tissue Doppler Parameters during Ultrasound Cardio-Vascular Investigation2007Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The department of Medical Technology, where I have done Master thesis project, develops and researches new method and technique within areas where ultrasound can be used to obtain the image of anatomical structure, functional capabilities and to suggest required treatment.

    Nowadays cardio-vascular diseases, such as infarct, atherosclerosis and ischemic syndrome, are one of the most widespread diseases in the world that’s why timely detection, identification and treatment are so important.

    The Master of Science qualification report consists 3 major parts: Medico-biological part, Design and Research parts.

    In Medico-biological part has been analyzed anatomical and physiological structure of the heart, current status of echocardiography with comparing with other techniques, summary of ultrasound methods with list of parameters that can be achieved is presented.

    In Design part has been developed new graphical modality based on Delta-V pump model using vector based statistical analysis for identification patients with ischemia. Software algorithm for automatically determine characteristic points for state diagram written in MatLab has been developed and implemented.

    In Research part in the first task using commercially available software based on Principal Component Analysis collected data from the hospital patients has been studied, results proved hypothesis concerning time variables importance; in the second task graphical module has been examined using collected data from the hospital patients both normal and with different cardio-vascular disease, and the results show good detection power of the algorithm.

    At the end of the project presentation has been done and report has been published.

    This project has been done in collaboration with the biggest medical institute in Sweden – Karolinska Institute - and results will be used in medical practice in Karolinska University Hospital in Huddinge and for future scientific needs.

     

  • 14.
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, Marcus Wallenberg Laboratory MWL.
    Polymer-shelled Ultrasound Contrast Agents: Characterization and Application2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ultrasound-based imaging technique is probably the most used approach for rapid investigationand monitoring of anatomical and physiological conditions of internal organs and tissues.Ultrasound-based techniques do not require the use of ionizing radiation making the tests anexceptionally safe and painless. Operating in the frequency range between 1 to 15 MHz, medicalultrasound provides reliable visual and quantitative information from both superficial structuressuch as muscles and tendons, and also deeper organs such as liver and kidney. From the technicalpoint of view medical ultrasound has a good spatial and temporal resolution. Ultrasound machineis mobile or even portable, which makes it truly bedside modality. And last but not the least,ultrasound investigations are cheaper in comparison to other real time imaging techniques.

    Ultrasound imaging techniques can be greatly improved by the use of contrast agents to enhancethe signal from the area of interest (e.g. cardiac or liver tissues) relative to the background.Typically ultrasound contrast agent (UCA) is a suspension of the microbubbles consisting of agas core encapsulated within the solid shell. Generally these devices are injected systemically andfunction to passively enhance the ultrasound echo. In recent years, the UCAs have evolved frombeing just a visualization tool to become a new multifunctional and complex device for drug orgene therapy and targeted imaging.

    The overall objective of the project is to test novel polymer shelled microbubbles (MBs) as apossible new generation of ultrasound contrast agents.

    During the first year of the project an innovative criterion based on cross-correlation analysis toassess the pressure threshold at which ultrasonic waves fracture the polymer shell of microbubblehas been developed. In addition, acoustic properties of these microbubbles which are relevant totheir use both as contrast agents and drug carriers for localized delivery have been preliminarytested. Furthermore, in order to reconstruct viscoelastic properties of the shell the originalChurch’s model (1995) has been implemented. In collaboration with Karolinska Institutet, imagesof the microbubbles have been acquired with conventional imaging system. These imagesdemonstrate the potential of the novel polymer-shelled microbubbles to be used as contractenhancing agents.

    The objective of the second year was to describe the acoustic and mechanical properties ofdifferent types of microbubbles synthesised under varied conditions. This task was divided in twointerrelated parts. In the first part acoustic characterization has been completed in low intensityregion with the study of backscattered power, attenuation and phase velocity. In order torecalculate mechanical properties of the shell existing theoretical model has been furtheriimodified to accommodate the frequency dependence of viscoelastic properties andsimultaneously fit the attenuation and phase velocity data. The results concerning acoustic andmechanical properties of the microbubbles have been sent as a feedback to the manufacture inorder to optimize fabrication protocol for effective image acquisition. In the second part acousticcharacterization has been performed in high intensity region under varied parameters ofexperimental set-up. The results that illustrate the dependence of the fracture pressure thresholdon the system parameters allows us to discuss the potential role of polymer-shelled UCAs as drugcarriers and formulate the protocol for save, localized, cavitation-mediated drug delivery.

    For the third year the major task was to move on from the bulk volume in vitro tests towards themicrocapillary study and even further to incorporate the microcapillary into the tissue mimickingultrasound phantom. The last study has the objective to take into account the wave propagationthrough tissue. And last but not the least, the application of the polymer-shelled microbubblesfor evaluation of perfusion characteristics, i.e. capillary volume and velocity of the flow, has beenperformed. Similar tests are carried out with commercially available phospholipid-shelled UCA.Using destruction/replenishment technique it is suggested that the novel polymer-shelledmicrobubbles have a potential for a more accurate perfusion evaluation compared to that ofcommercially available phospholipid-shelled UCA.

    In conclusion, proposed polymer-shelled gas-core microbubbles provide a viable system to beused among the next generation of ultrasound contrast agents, which facilitate not only imageenhancement relevant to diagnostics but also localized and specific drug delivery for non-invasivetherapy even in acute conditions.

  • 15.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering.
    Three modality contrast imaging using multi-functionalized microballoons2011Conference paper (Refereed)
    Abstract [en]

    In vivo multimodality imaging is a fast growing field in medical research and, although the achievements at clinical level of this diagnostic method are recent, it is already one of the most promising approaches in the diagnosis of diseases in many research addressed medical centres. At present in this area, the USA plays the protagonist role as a result of the amount of resources engaged in the arena in the last decade. Both government and private companies agree, when considering the potential of this approach, that it is one of the foremost medical advancements as it will lead to early diagnosis of diseases with high impact on the societies of western countries. Multimodality imaging is currently viewed as a simple and powerful integration of two or more imaging methods (e.g. PET-CT). 3MICRON is an ambitious project which gathers some of the most advanced European medical and technical institutions together to address the design of new strategies in diagnostics, and to push the potential of medical imaging beyond the state-of-the-art. The multimodality approaches are supported by a class of next-generation micro/nanodevices called microballoons. These subsystems are able to implement the function of an ultrasound contrast agent with other imaging methods (SPECT, MRI). In the future, they may act as a minimally invasive drug delivery method and hyperthermia device. In 3MICRON, this multi-functional device will be tested in vitro and in vivo in order to assess bioclearance and cytoxicity effects toward high impact diseases, e.g. cardiovascular and inflammation pathologies. Finally, selected types of microballoons will undergo pre-clinical screening for a consolidated assessment of the “bench-to-bed” pathway for these new microdevices.

  • 16.
    Grishenkov, Dmitry
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institute, Sweden.
    Adrian, Gonon
    Karolinska University Hospital, Sweden.
    Janerot Sjöberg, Birgitta
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institute, Sweden.
    In search of the optimal ultrasound heart perfusion imaging platform2015In: Journal of ultrasound in medicine, ISSN 0278-4297, E-ISSN 1550-9613, Vol. 34, no 9, p. 1599-1605Article in journal (Refereed)
    Abstract [en]

    Objective

    Quantification of the myocardial perfusion by contrast echocardiography (CEC) remains a challenge. Existing imaging phantoms used to evaluate the performance of ultrasound scanners do not comply with perfusion basics in the myocardium, where perfusion and motion are inherently coupled.

    Methods

    To contribute towards an improvement, we developed a CEC perfusion imaging platform based on isolated rat heart coupled to the ultrasound scanner. Perfusion was assessed using three different types of contrast agent: dextran-based Promiten®, phospholipid-shelled SonoVue®, and polymer-shelled MB-pH5-RT. The myocardial video-intensity was monitored over time from contrast administration to peak and two characteristic constants were calculated using exponential fit (A representing capillary volume and b representing inflow velocity).

    Results

    Acquired experimental evidence demonstrates that the application of all three types of contrast agent allow ultrasonic estimation of myocardial perfusion in the isolated rat heart. Video-intensity maps show that an increase in contrast concentration increases the late plateau values, A, mimicking increased capillary volume. Estimated values of the flow, proportional to Axb, increase when the pressure of the perfusate column increases from 80 to 110 cm of water. This finding is in agreement with the true values of the coronary flow increase measured by the flowmeter attached to the aortic cannula.

    Conclusions

    The described CEC perfusion imaging platform holds promise for standardized evaluation and optimization of ultrasound contrast perfusion imaging where real time inflow curves at low acoustic power semi-quantitatively reflect coronary flow.

  • 17.
    Grishenkov, Dmitry
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institutet (KI), CLINTEC – Division of Medical Imaging and Technology.
    Adrian, Gonon
    Department of Clinical Physiology, Karolinska University Hospital.
    Weitzberg, Eddie
    Department of Physiology and Pharmacology, Karolinska Institutet.
    Lundberg, Jon
    Department of Physiology and Pharmacology, Karolinska Institutet, .
    Harmark, Johan
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.
    Cerroni, Barbara
    Department of Chemical Sciences and Technologies, University of Rome Tor Vergata.
    Paradossi, Gaio
    Diapartimento di Chimica, Università di Roma Tor Vergata.
    Janerot Sjöberg, Birgitta
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. CLINTEC, Department of Medical Imaging and Technology, Karolinska Institute.
    Ultrasound contrast agent loaded with nitric oxide as a theranostic microdevice: Theranostic contrast agent loaded with nitric oxide2015In: Drug Design, Development and Therapy, ISSN 1177-8881, E-ISSN 1177-8881, Vol. 9, p. 2409-2419Article in journal (Refereed)
    Abstract [en]

    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.

  • 18.
    Grishenkov, Dmitry
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering.
    Brodin, Lars-Åke
    KTH, School of Technology and Health (STH), Medical Engineering.
    Brismar, Torkel B.
    CLINTEC, Department of Radiology, Karolinska University Hospital.
    Paradossi, Gaio
    Dipartimento di Chimica, Università di Roma Tor Vergata.
    On comparison between polymer- and phospholipid-shelled microbubbles for contrast-enhanced ultrasound measurements of capillary microcirculation.2011In: Proceedings of the 34th Scandinavian Symposium on Physical Acoustics / [ed] Rolf J. Korneliussen, 2011Conference paper (Refereed)
    Abstract [en]

    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.

  • 19.
    Grishenkov, Dmitry
    et al.
    Karolinska Institutet (KI), CLINTEC – Division of Medical Imaging and Technology.
    Gonon, Adrian
    Paradossi, Gaio
    Diapartimento di Chimica, Università di Roma Tor Vergata.
    Janerot Sjöberg, Birgitta
    CLINTEC, Department of Medical Imaging and Technology, Karolinska Institute.
    Ultrasound contrast agent loaded with nitric oxide as a theranostic microdevise for myocardial ischemia2013Conference paper (Refereed)
    Abstract [en]

    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 withmortality exponentially increasing with age. Efforts of healthcare system should be primary focused on prevention, timely detection, efficient differentiation and instant treatment of the disease.

  • 20.
    Grishenkov, Dmitry
    et al.
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, MWL Ultrasound.
    Kari, Leif
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, Marcus Wallenberg Laboratory MWL.
    Brismar, Torkel B.
    Karolinska University Hospital.
    Paradossi, Gaio
    Università di Roma Tor Vergata.
    Acoustic properties of polymer-shelled ultrasound contrast agents. Bulk volume vs. microcapillary2009In: 16th International Congress on Sound and Vibration 2009, ICSV 2009, Krakow, 2009, p. 2515-2522Conference paper (Refereed)
    Abstract [en]

    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.

  • 21.
    Grishenkov, Dmitry
    et al.
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, Marcus Wallenberg Laboratory MWL.
    Kari, Leif
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, MWL Structural and vibroacoustics.
    Brodin, Lars-Åke
    KTH, School of Technology and Health (STH), Medical Engineering.
    Brismar, Torkel B.
    CLINTEC, Department of Radiology, Karolinska Institutet.
    Paradossi, Gaio
    Dipartimento di Chimica, THE UNIVERSITY OF ROME.
    In vitro contrast-enhanced ultrasound measurements of capillary microcirculation: Comparison between polymer- and phospholipid-shelled microbubbles2011In: Ultrasonics, ISSN 0041-624X, E-ISSN 1874-9968, Vol. 51, no 1, p. 40-48Article in journal (Refereed)
    Abstract [en]

    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.

  • 22.
    Grishenkov, Dmitry
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Kothapalli, Veeravenkata S.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Gonon, Adrian
    Karolinska University Hospital, Huddinge, Sweden .
    Janerot Sjöberg, Birgitta
    CLINTEC, Department of Medical Imaging and Technology, Karolinska Institute.
    Ultrasound contrast agent loaded with nitric oxide as a theranostic microdevise for myocardial ischemia2013In: European Heart Journal Cardiovascular Imaging: Abstracts of EUROECHO 2013 The Seventeenth Annual Meeting of the European Association of Echocardiography, 2013Conference paper (Refereed)
    Abstract [en]

    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.

  • 23.
    Grishenkov, Dmitry
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering.
    Paradossi, Gaio
    Diapartimento di Chimica, Università di Roma Tor Vergata.
    Assessment of ultrasound-induced fracture of polymer-shelled ultrasound contrast agents using superharmonic technique2012Conference paper (Refereed)
    Abstract [en]

    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.

  • 24.
    Grishenkov, Dmitry
    et al.
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, MWL Ultrasound.
    Pecorari, Claudio
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, MWL Ultrasound.
    Brismar, Torkel B.
    Karolinska University Hospital.
    Paradossi, Gaio
    Università di Roma Tor Vergata.
    Characterization of Acoustic Properties of PVA-Shelled Ultrasound Contrast Agents2010In: Ultrasound Contrast Agents: Targeting And Processing Methods For Theranostics / [ed] G. Paradosi, P. Pellegretti, A. Trucco, Italia: Springer-Verlag , 2010, p. 99-108Chapter in book (Other academic)
    Abstract [en]

    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.

  • 25.
    Grishenkov, Dmitry
    et al.
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, Marcus Wallenberg Laboratory MWL.
    Pecorari, Claudio
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering. KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, Marcus Wallenberg Laboratory MWL.
    Brismar, Torkel B.
    Paradossi, Gaio
    Characterization of acoustic properties of PVA-shelled ultrasound contrast agents: linear properties (Part I)2009In: Ultrasound in Medicine and Biology, ISSN 0301-5629, E-ISSN 1879-291X, Vol. 35, no 7, p. 1127-1138Article in journal (Refereed)
    Abstract [en]

    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.

  • 26.
    Grishenkov, Dmitry
    et al.
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, Marcus Wallenberg Laboratory MWL.
    Pecorari, Claudio
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering.
    Brismar, Torkel B.
    Paradossi, Gaio
    Characterization of acoustic properties of PVA-shelled ultrasound contrast agents: ultrasound-induced fracture (Part II)2009In: Ultrasound in Medicine and Biology, ISSN 0301-5629, E-ISSN 1879-291X, Vol. 35, no 7, p. 1139-1147Article in journal (Refereed)
    Abstract [en]

    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.

  • 27.
    Grishenkov, Dmitry
    et al.
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, MWL Ultrasound.
    Pecorari, Claudio
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, MWL Ultrasound.
    Brismar, Torkel B.
    Karolinska University Hospital.
    Paradossi, Gaio
    Università di Roma Tor Vergata.
    On the acoustic properties of polymer-shell ultrasonic contrast agents.2008Conference paper (Other academic)
    Abstract [en]

    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.

  • 28.
    Janerot Sjöberg, Birgitta
    et al.
    CLINTEC, Department of Medical Imaging and Technology, Karolinska Institute.
    Gonon, Adrian
    tutet (KI), Dept of Medicine.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institutet (KI), CLINTEC – Division of Medical Imaging and Technology.
    In Search of the Optimal Ultrasound Heart Perfusion Imaging Platform2013Conference paper (Refereed)
  • 29.
    Kothapalli, Satya V. V. N.
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Brodin, Lars-Åke
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Paradossi, Gaio
    Dynamic and Structural Behavior of Magnetic PVA-Shelled Microbubbles: Acoustic Characterization2013In: IEEE International Ultrasonics Symposium / [ed] Dr. AHMAD SAFARI, 2013, p. 1509-1512Conference paper (Refereed)
    Abstract [en]

    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).

  • 30.
    Kothapalli, Satya V. V. N.
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering.
    Wiklund, Martin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Janerot-Sjöberg, Birgitta
    KTH, School of Technology and Health (STH), Medical Engineering. Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Paradossi, Gaio
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering. Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Investigation of polymer-shelled microbubble motions in acoustophoresis2016In: Ultrasonics, ISSN 0041-624X, E-ISSN 1874-9968, Vol. 70, p. 275-283Article in journal (Refereed)
    Abstract [en]

    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.

  • 31.
    Kothapalli, Satya V.V.N.
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Wiklund, Martin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Janerot Sjöberg, Birgitta
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden .
    Paradossi, Gaio
    Diapartimento di Chimica, Università di Roma Tor Vergata.
    Brodin, Lars-Åke
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden .
    Investigation of Polymer-Shelled Microbubble Motions in AcoustophoresisManuscript (preprint) (Other academic)
    Abstract [en]

    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.

  • 32.
    Kothapalli, Veera Venkata Satya Naray
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Daeichin, Verya
    Department of Biomedical Engineering, Thoraxcenter, Erasmus MC,.
    Mastik, Frits
    Department of Biomedical Engineering, Thoraxcenter, Erasmus MC.
    Brodin, Lars-Åke
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Janerot Sjöberg, Birgitta
    KTH, School of Technology and Health (STH), Medical Engineering. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden .
    Paradossi, Gaio
    Diapartimento di Chimica, Università di Roma Tor Vergata.
    de Jong, N.
    Department of Biomedical Engineering, Thoraxcenter, Erasmus MC.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden .
    Unique pumping-out fracturing mechanism of a polymer-shelled contrast agent: An acoustic characterization and optical visualization2014In: IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, ISSN 0885-3010, E-ISSN 1525-8955, Vol. 62, no 3, p. 451-462, article id 7055440Article in journal (Refereed)
    Abstract [en]

    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.

  • 33.
    Kothapalli, Veera Venkata Satya Naray
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering.
    Faridi, Asim
    Wiklund, Martin
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institutet (KI), CLINTEC – Division of Medical Imaging and Technology.
    On-chip actuation of polymer shelled microbubbles2013Conference paper (Other academic)
  • 34.
    Kothapalli, Veera Venkata Satya Naray
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering.
    Optimization of driving pulse envelopes in detection of harmonic response from lipid-shelled ultrasound contrast agent2012In: 19th International Congress on Sound and Vibration 2012, ICSV 2012: Volume 3, 2012, 2012, p. 1882-1889Conference paper (Refereed)
    Abstract [en]

    The assessment of the harmonic response is commonly used in analysis of the signals from ultrasound contrast agents (UCAs). Theoretical and experimental studies report that acoustic behavior of UCAs strongly depends on insonation pressure. Other system parameters, such as the number of cycles, driving and repetition frequency and the pulse shape are equally important. The major focus of this work is to investigate the effect of the shape of driving pulse envelopes on detection of second- (2f), super- (3f, 4f, 5f), sub- (f/2), and ultra-harmonics (3f/2). In this paper, numerical simulations on thin-shelled lipidic UCA have been performed. The simulation results indicate that, high sidelobe suppression envelopes (e.g. 4-term Blackman-Harris), manage to detect second and third harmonic with harmonic-to-fundamental ratio (HFR) of 32 and 69 dB, respectively, at low acoustic pressure of 5 kPa. However, conventional low sidelobe suppression envelopes (e.g. rectangular, cos-tapered, Hanning, Gaussian) fail to identify the harmonic response. Yet the increase of the insonation pressure to 200 kPa leads to increase of the broadband noise. This negatively effects the frequency resolution when high suppression sidelobe envelopes are applied to the driving pulse. As a result, the application of conventional envelopes in harmonic response detection at intermediate acoustic pressure, is recommended. It is also worth mentioning, that at high isonation pressure of 0.9 MPa, cos-tapered envelope, having a side lobe fall-off equal to 18 dB/octave, is able to identify the sub- and ultra-harmonics. In conclusion our study demonstrates that the driving pulse envelope should be selected according to the incident pressure for the complete exploitation of the unique nonlinear signature from UCA. A compromise could be found with the application of adjustable Kaiser-Bessel envelope where by varying the β parameter from 0 to 10 one goes from low to high sidelobe suppression envelope.

  • 35.
    Kothapalli, Veera Venkata Satya Naray
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering.
    Brodin, Lars-Åke
    KTH, School of Technology and Health (STH), Medical Engineering.
    Paradossi, Gaio
    Diapartimento di Chimica, Università di Roma Tor Vergata.
    Coded Excitation Technique in Detection of Polymeric-Shelled Ultrasound contrast Agents: in Vitro Study2011In: 8th International Conference on Nanosciences & Nanotechnologies (NN11) 12-15 July 2011, Thessaloniki, Greece.: Workshop: NANOMEDICINE, 2011Conference paper (Refereed)
    Abstract [en]

    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. 

  • 36.
    Kothapalli, Veeravenkata S.
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Oddo, L.
    Paradossi, G.
    Brodin, Lars-Åke
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Assessment of the viscoelastic and oscillation properties of a nanoengineered-shelled multimodality contrast agentManuscript (preprint) (Other academic)
  • 37.
    Kothapalli, Veeravenkata S.
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Oddo, Letizia
    Paradossi, Gaio
    Brodin, Lars- Åke
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Inst, Sweden.
    Assessment of the Viscoelastic and Oscillation Properties of a Nano-engineered Multimodality Contrast Agent2014In: Ultrasound in Medicine and Biology, ISSN 0301-5629, E-ISSN 1879-291X, Vol. 40, no 10, p. 2476-2487Article in journal (Refereed)
    Abstract [en]

    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.

  • 38.
    Kothapalli, Veeravenkata Satya
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Paradossi, Gaio
    Diapartimento di Chimica, Università di Roma Tor Vergata.
    Brodin, Lars-Åke
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institutet (KI), CLINTEC – Division of Medical Imaging and Technology.
    Dynamic and Structural behavior of Magnetized PVA-shelled Microbubbles: Acoustic Characterization2013Conference paper (Refereed)
  • 39.
    Loskutova, Ksenia
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Ghorbani, Morteza
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging. Mechatronics Engineering Program, Faculty of Engineering and Natural Science, Sabanci University, Istanbul 34956, Turkey.
    Review on Acoustic Droplet Vaporization in Ultrasound Diagnostics and Therapeutics2019In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, article id 9480193Article, review/survey (Refereed)
    Abstract [en]

    Acoustic droplet vaporization (ADV) is the physical process in which liquid undergoes phase transition to gas after exposure to a pressure amplitude above a certain threshold. In recent years, new techniques in ultrasound diagnostics and therapeutics have been developed which utilize microformulations with various physical and chemical properties. The purpose of this review is to give the reader a general idea on how ADV can be implemented for the existing biomedical applications of droplet vaporization. In this regard, the recent developments in ultrasound therapy which shed light on the ADV are considered. Modern designs of capsules and nanodroplets (NDs) are shown, and the material choices and their implications for function are discussed. The influence of the physical properties of the induced acoustic field, the surrounding medium, and thermophysical effects on the vaporization are presented. Lastly, current challenges and potential future applications towards the implementation of the therapeutic droplets are discussed.

  • 40.
    Pecorari, Claudio
    et al.
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, MWL Ultrasound.
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, MWL Ultrasound.
    Characterization of ultrasound-induced fracture of polymer-shelled ultrasonic contrast agents by correlation analysis2008Conference paper (Other academic)
  • 41.
    Pecorari, Claudio
    et al.
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, Marcus Wallenberg Laboratory MWL.
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, Marcus Wallenberg Laboratory MWL.
    Characterization of ultrasound-induced fracture of polymer-shelled ultrasonic contrast agents by correlation analysis2007In: Journal of the Acoustical Society of America, ISSN 0001-4966, E-ISSN 1520-8524, Vol. 122, no 4, p. 2425-2430Article in journal (Refereed)
    Abstract [en]

    Beyond a characteristic value of the negative peak pressure, ultrasound fracture the shell of ultrasonic contrast agents (UCAs). Existing criteria for ascertaining this threshold value exploit the dependence of the amplitude of the UCA acoustic response on the incident pressure. However, under the common experimental conditions used in this work, these criteria appear to be unreliable when they are applied to UCAs that are stabilized by a thick polymeric shell. An alternative criterion for determining the onset of shell fracture is introduced here, which uses variations of the shape of the acoustic time-domain response of an UCA suspension. Experimental evidence is presented that links the changes of the cross-correlation coefficient between consecutive time-domain signals to the fracture of the shells, and consequent release of air microbubbles. In principle, this criterion may be used to characterize similar properties of other types of particles that cannot undergo inertial cavitation.

  • 42.
    Poehlman, Melanie
    et al.
    University Baureight.
    Kothapalli, Veera Venkata Satya Naray
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Institutet (KI), CLINTEC – Division of Medical Imaging and Technology.
    Härmark, Johan
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.
    Hebert, Hans
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.
    Philipp, A.
    Hoeller, Roland
    Seuss, M.
    Magerithelli, S.
    Paradossi, Gaio
    Diapartimento di Chimica, Università di Roma Tor Vergata.
    Fery, Andreas
    Magnetic microbubbles for multimodality imaging: the importance of the shell structure for low and high frequency mechanics2013Conference paper (Refereed)
    Abstract [en]

    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.

  • 43. Poehlmann, Melanie
    et al.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Kothapalli, Satya V.V.N.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Härmark, Johan
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.
    Hebert, Hans
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.
    Philipp, Alexandra
    Hoeller, Roland
    Seuss, Maximilian
    Kuttner, Christian
    Margheritelli, Silvia
    Paradossi, Gaio
    Frey, Andreas
    On the interplay of shell structure with low- and high-frequency mechanics of multifunctional magnetic microbubbles2014In: Soft Matter, ISSN 1744-683X, E-ISSN 1744-6848, Vol. 10, no 1, p. 214-226Article in journal (Refereed)
    Abstract [en]

    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.

  • 44. Sciallero, Claudia
    et al.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Kothapalli, Satya V. V. N.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Oddo, Letizia
    Trucco, Andrea
    Acoustic characterization and contrast imaging of microbubbles encapsulated by polymeric shells coated or filled with magnetic nanoparticles2013In: Journal of the Acoustical Society of America, ISSN 0001-4966, E-ISSN 1520-8524, Vol. 134, no 5, p. 3918-3930Article in journal (Refereed)
    Abstract [en]

    The combination of superparamagnetic iron oxide nanoparticles with polymeric air-filled microbubbles is used to produce two types of multimodal contrast agents to enhance medical ultrasound and magnetic resonance imaging. The nanoparticles are either covalently linked to the shell or physically entrapped into the shell. In this paper, the characterization of the acoustic properties (backscattered power, fracturing pressure, attenuation and dispersion of the ultrasonic wave) and ultrasound imaging of the two types of magnetic microbubbles are presented. In vitro B-mode images are generated using a medical ultrasound scanner by applying a nonconventional signal processing technique that is suitable to detect polymeric bubbles and based on the combination of multipulse excitation and chirp coding. Even if both types of microbubbles can be considered to be effective ultrasound contrast agents, the different structure of the shell loaded with nanoparticles has a pronounced effect on the echogenicity and the detection sensitivity of the imaging technique. The best results are obtained using microbubbles that are externally coated with nanoparticles. A backscattered power of 20 dB was achieved at lower concentration, and an increment of 8 dB in the contrast-to-tissue ratio was observed with respect to the more rigid microbubbles with particles entrapped into the shell.

  • 45. Tamadapu, Ganesh
    et al.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Eriksson, Anders
    Modeling and parametric investigation of thick encapsulated microbubble's nonspherical oscillations2016In: Journal of the Acoustical Society of America, ISSN 0001-4966, E-ISSN 1520-8524, Vol. 140, no 5, p. 3884-3895Article in journal (Refereed)
    Abstract [en]

    Numerous studies have been carried out in the past few decades to investigate the radial oscillations of encapsulated microbubbles (MBs). Nonspherical oscillations also have gained attention, being unavoidable in actual applications of these bubbles. The present paper is intended to describe the nature of resonance trends of such spherical and nonspherical modes of a thick encapsulated MB filled with air and suspended in water. The shell material is assumed to be linear viscoelastic and quasi-incompressible. The considered isotropic and spherically isotropic material parametric range is limited to thick polymer shelled MBs. For the case of an isotropic material, shell viscosity has a major influence on the fundamental modes with meridional wave number n = 0, 4, especially for thicker bubbles, unlike for the case of the spherically isotropic material case considered, where the viscosity has very little influence. For most of the parametric range, n = 2, 3 modes are underdamped and their frequency is found to be lower than the n = 0, 4 modes, for both material cases. An interesting case is found for a spherically isotropic quasiincompressible material case, where the first few nonspherical mode resonances are very close to radial mode resonance frequency.

  • 46. Toumia, Y.
    et al.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering. Karolinska Institutet (KI), CLINTEC – Division of Medical Imaging and Technology.
    Graphene Meets Microbubbles: A Superior Contrast Agent for Photoacoustic Imaging2016In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 8, no 25, p. 16465-16475Article in journal (Refereed)
    Abstract [en]

    Coupling graphene with a soft polymer surface offers the possibility to build hybrid constructs with new electrical, optical, and mechanical properties. However, the low reactivity of graphene is a hurdle in the synthesis of such systems which is often bypassed by oxidizing its carbon planar structure. However, the defects introduced with this process jeopardize the properties of graphene. In this paper we present a different approach, applicable to many different polymer surfaces, which uses surfactant assisted ultrasonication to exfoliate, and simultaneously suspend, graphene in water in its intact form. Tethering pristine graphene sheets to the surfaces is accomplished by using suitable reactive functional groups of the surfactant scaffold. We focused on applying this approach to the fabrication of a hybrid system, made of pristine graphene tethered to poly(vinyl alcohol) based microbubbles (PVA MBs), designed for enhancing photoacoustic signals. Photoacoustic imaging (PAI) is a powerful preclinical diagnostic tool which provides real time images at a resolution of 40 μm. The leap toward clinical imaging has so far been hindered by the limited tissues penetration of near-infrared (NIR) pulsed laser radiation. Many academic and industrial research laboratories have met this challenge by designing devices, each with pros and cons, to enhance the photoacoustic (PA) signal. The major advantages of the hybrid graphene/PVA MBs construct, however, are (i) the preservation of graphene properties, (ii) biocompatibility, a consequence of the robust anchoring of pristine graphene to the bioinert surface of the PVA bubble, and (iii) a very good enhancement in a NIR spectral region of the PA signal, which does not overlap with the signals of PA active endogenous molecules such as hemoglobin.

  • 47.
    Zheng, Miaomiao
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering.
    Härmark, Johan
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.
    Grishenkov, Dmitry
    KTH, School of Technology and Health (STH), Medical Engineering.
    Janerot Sjöberg, Birgitta
    CLINTEC, Department of Medical Imaging and Technology, Karolinska Institute.
    Polymer-Shelled Ultrasound Contrast Agents with controlled size and polydispersity.2011In: Nanomedicine: Nanotechnology, Biology & Medicine, 2011Conference paper (Refereed)
    Abstract [en]

    Ultrasound imaging techniques can be greatly improved by the use of ultrasound contrast agents (UCAs). Gas bubbles encapsulated into biocompatible polymer shell are of particular interest of this work. Shell of the bubbles produced from Poly-Vinyl-Alcohol (PVA) offers considerable chemical versatility and stability. However, questions regarding the size and polydispersity of the microbubbles must be further investigated. The ideal UCAs should not obstruct the blood flow in pulmonary capillaries which diameter is less than 10 μm. From the technical perspective UCAs should modify the acoustic properties of a region of interest, by increasing backscattered efficiency. In order to enhance the ultrasound response UCAs should be engineered with narrow size distribution. In the present work PVA-shelled UCAs with controlled size and polydispersity is manufactured under varied parameters of the manufacturing protocol. It was observed that temperature of the surrounding atmosphere has major effect on the size of the UCAs, while polydispersity is regulated by geometry and speed of the disperser. Finally, the acoustic response of these microbubbles is tested using developed ultrasound test rig. The enhancement of the backscattered power of about 25 dB from a suspension of the microbubbles is observed at 5 MHz ultrasound frequency. Keeping in mind that in clinical practice ultrasound scatter from the blood is of about 30 dB weaker than scatter from surrounding tissue, introduction of novel PVA microbubbles will potentially improve diagnosis of the cardiovascular patients.

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