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  • 1.
    Abbasiasl, Taher
    et al.
    Sabanci University.
    Niazi, Soroush
    Sabanci University.
    Sheibani Aghdam, Araz
    Sabanci University.
    Chen, Hongjian
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Cebeci, Fevzi Cakmak
    Sabanci University.
    Ghorbani, Morteza
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging. 1 Sabanci University Nanote.
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Kosar, Ali
    Sabanci University.
    Effect of intensified cavitation using poly (vinyl alcohol) microbubbles on spray atomization characteristics in microscale2020In: AIP Advances, E-ISSN 2158-3226, Vol. 10, no 2Article in journal (Refereed)
    Abstract [en]

    In this study, cavitating flows inside a transparent cylindrical nozzle with an inner diameter of 0.9 mm were visualized, and the effect of cavitation on atomization characteristics of emerging sprays was investigated. Different patterns of cavitating flows inside the nozzle were visualized using a high-speed camera. In-house codes were developed to process the captured images to study the droplet size distribution and droplet velocity in different flow regimes. The results show that cavitating flows at the microscale have significant effects on atomization characteristics of the spray. Two working fluids, namely, water and poly(vinyl alcohol) microbubble (PVA MB) suspension, were employed. Accordingly, the injection pressures were detected as 690 kPa, 1035 kPa, and 1725 kPa for cavitation inception, supercavitation, and hydraulic flip flow regimes in the case of water, respectively. The corresponding pressures for the aforementioned patterns for PVA MB suspension were 590 kPa, 760 kPa, and 1070 kPa, respectively. At the microscale, as a result of a higher volume fraction of cavitation bubbles inside the nozzle, there is no large difference between the cavitation numbers corresponding to cavitating and hydraulic flip flows. Although the percentage of droplets with diameters smaller than 200 μm was roughly the same for both cases of water and PVA MB suspension, the Sauter mean diameter was considerably lower in the case of PVA MBs. Moreover, higher droplet velocities were achieved in the case of PVA MBs at lower injection pressures.

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  • 2. 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.

  • 3. 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.

  • 4. 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.

  • 5.
    Chen, Hongjian
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Evangelou, Dimitrios
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems. KTH Royal Inst Technol, Dept Biomed Engn & Hlth Syst, S-14152 Stockholm, Sweden..
    Loskutova, Ksenia
    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. Sabanci Univ, Nanotechnol Res & Applicat Ctr, TR-34956 Istanbul, Turkey..
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging. Karolinska Inst, Dept Clin Sci Intervent & Technol, S-14152 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Physiol, S-17177 Stockholm, Sweden..
    On the Development of a Novel Contrast Pulse Sequence for Polymer-Shelled Microbubbles2021In: IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, ISSN 0885-3010, E-ISSN 1525-8955, Vol. 68, no 5, p. 1569-1579Article in journal (Refereed)
    Abstract [en]

    Contrast agents are routinely used in ultrasound examinations. Nonlinear ultrasound imaging techniques have been developed over decades to enhance the contrast between the tissue and the blood pool after the injection of ultrasound contrast agents (UCAs). In this study, we introduce a new contrast pulse sequence, CPS4. The CPS4 combines pulse inversion (PI), subharmonic (SH), and ultraharmonic (UH) techniques to remove propagation distortion while capturing the unique SH and UH responses from UCAs. The novel CPS4 and conventional PI, SH, and UH techniques were used to detect the presence of a research-grade, thick-shell, polymer microbubble in a tissue-mimicking flow phantom. The contrast-to-tissue ratios (CTRs) obtained from the applications of all techniques were compared. The results show that the highest CTR of approximately 16 dB was obtained using CPS4, which was superior to the individual reference techniques: PI, SH, and UH techniques, in all scenarios considered in this study.

  • 6.
    Chen, Hongjian
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Evangelou, Dimitrios
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems.
    Loskutova, Ksenia
    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.
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    On the Development of a Novel Contrast Pulse Sequence for Polymer-Shelled MicrobubblesIn: IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, ISSN 0885-3010, E-ISSN 1525-8955Article in journal (Refereed)
    Abstract [en]

    Contrast agents are routinely used in ultrasound examinations. Nonlinear ultrasound imaging techniques have been developed over decades to enhance the contrast between the tissue and the blood pool after the injection of ultrasound contrast agents. In this study, we introduce a new contrast pulse sequence, CPS4. The CPS4 combines pulse inversion, sub-harmonic, and ultra-harmonic techniques to remove propagation distortion while capturing the unique sub-harmonic, and ultra-harmonic responses from ultrasound contrast agents. The novel CPS4 and conventional pulse inversion, sub-harmonic, and ultra-harmonic techniques were used to detect the presence of a research-grade, thick shell, polymer microbubble in a tissue-mimicking flow phantom. The contrast-to-tissue ratio (CTR) obtained from the applications of all techniques were compared. The results show that the highest CTR of approximately 16 dB was obtained using CPS4, which was superior to the individual reference techniques: pulse inversion, sub-harmonic, and ultra-harmonic techniques, at all scenarios considered in this study.

  • 7.
    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.

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  • 8.
    Chen, Hongjian
    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.
    A mathematical model of polyvinyl alcohol microbubbles2020Conference paper (Refereed)
    Abstract [en]

    Microbubbles (MBs) as ultrasound contrast agents (UCAs) are increasingly accepted in the medical diagnostics. Their unique acoustic features enable the efficient detection of the MBs at a very low volume fraction. An improved understanding of the MBs dynamics could accelerate the development of UCA detection, i.e., enhanced ultrasound imaging techniques. Thereby, considerable efforts were dedicated to establishing models to interpret the dynamics of the microbubbles.

    The joint endeavors of Rayleigh[1], Plesset[2], and other researchers led to the Rayleigh-Plesset equation, which describes the dynamics of the free MBs. The free MBs as a UCA has limited value because of their short lifespan in the human body. Additional coatings around the gas core with various materials were employed to extend the lifespan of the MBs. As a result, the models of the MBs evolved to explain the effects of the encapsulation. At the same time, many simplified assumptions were made. However, the diversity and the complexity of the MBs shell make some simplified assumptions invalided.

    For instance, the polyvinyl alcohol (PVA) shell of the PVA MBs is heterogeneous and exhibit frequency-dependent mechanical properties, which were often neglected in previous studies.

  • 9.
    Chen, Hongjian
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Larsson, David
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Janerot-Sjöberg, Birgitta
    Colarieti-Tosti, Massimiliano
    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.
    Polymer Microbubbles as Dual Modal Contrast Agent for Ultrasound and Computed Tomography2018Conference paper (Refereed)
    Abstract [en]

    The hybrid imaging combines the anatomical information with the functional or metabolic information using different conventional single imaging modalities improving the overall diagnosis outcome of the clinical examination. Since the introduction of the first hybrid imaging device PET-CT in 1998 different combinations of hybrid imaging were developed such as PET-MRI, SPECT-CT.

    However, lack of multimodal contrast agent specifically aimed for hybrid imaging limits the diagnostic outcome of these novel techniques. Initial attempts in fabrication of hybrid contrast agents were made by combining previously existing single modal contrast agents into one. In this study, polyvinyl alcohol (PVA) microbubbles (MB) and gold nanoparticles - which by themselves are already established contrast agents used in preclinical studies for ultrasound and CT, respectively - were chosen as parent contrast agents to fabricate the dual modal Contrast Agent for UltraSound and CT (CACTUS).

    Method

    The fabrication of MBs was adapted from Cavalieri et al.[1]. PVA powder (Sigma Aldrich, MO USA) was dissolved in the water at 80°C. The aqueous PVA-chains were cleaved by sodium metaperiodate (NaIO4, purity>99.0%, Sigma Aldrich, MO USA). Vigorous stirring force was applied to the resulting telechelic aldehydic PVA-chains for 2 hours to crosslink the telechelic aldehydic PVA-chains and form the PVA-coated MBs at the water-air interface.

    CACTUS MBs were synthesized in a similar fashion to the above, but adding gold nanoparticles (diameter 1.9nm, Nanoprobes, NY, USA) during formation of the MBs.

    The size distributions of MBs and CACATUS MBs were determined using an optical microscope (ECLIPSE Ci-S, Nikon, Tokyo, Japan) and a Neubauer counting chamber (Brand GmbH, Wertheim, Germany).

    The acoustic attenuation coefficients of the MBs suspension were acquired at peak negative pressure (PNP) from 10 - 300 kPa. Three MBs suspension samples with concentrations of (sample A),  (sample B) and  ml-1 (sample C) were prepared and loaded in a 1 cm thick two-cavity chamber. A flat single crystal ultrasound transducer with central frequency 3.5MHz was used to generate the ultrasound beam. The amplitude of received echoes through samples and water were compared at the fundamental frequency, as well as the 2nd and 3rd harmonic for each value of the concentration used.

    The mass attenuation of water, suspension of gold nanoparticles with concentration 160mg/L, plain MBs, and CACTUS MBs, was measured by quantum FX-CT micro-CT (PerkinElmer Inc, MA, USA). The micro-CT was operated at a current of 200mA with exposure time of 120s and varied voltage 50kV, 70kV and 90kV. Each 3D image has a size of 512*512*512 pixels or 75.8*75.8*75.8 mm. Contrast to noise ratios (CNR) between water and all samples were calculated following Eq. 1.Where S(x,y,z) and W(x,y,z) are the mass attenuation of the sample and water per voxel, respectively. ns(x,y,z) and nw(x,y,z) are the noise function with zero mean of sample and water respectively. Ms and Mw are the mean mass attenuation acquired for the sample and water in the volume of interest. The σs2 and σw2 are the variance of the mass attenuation read out of the sample and water in the volume of interested.

    In addition to the gas-core MBs for the CT tests, liquid-core gold loaded capsules were synthesized in two steps. In the first step, PVA shelled liquid-core capsules were obtained by exposing MBs to 66% v/v ethanol solution. In the second step, the resulting liquid-core capsules were mixed with high concentration gold nanoparticles suspension and homogenized by a shaker (MS 3 basic, IKA, Königswinter Germany) at 500rpm for 1 hour for goal loading. The resulting gold loaded capsules were washed with Milli-Q water using centrifuge (Galaxy 5D digital microcentrifuge, VWR, USA) at a speed of 1000 g for 5 min.

    Results and discussion

    The mean diameter of MBs is 3.6±1.1 μm. The mean diameter of CACTUS MBs is 3.2±0.7 μm. The size distribution of the gold loaded capsules was not investigated separately, but rather assumed identical to the plain MBs. The number and the volume distribution of MBs and CACTUS MBs are shown in figure 1. The results demonstrate that most of the CACTUS MBs and MBs have a diameter from 1 to 6 μm. Therefore, they are able pass through the capillaries and will resonate within typical clinical diagnostic ultrasound frequency below 15 MHz.

    Pressure dependent acoustic attenuation coefficients of the sample A, B, and C are shown in figure 2. The results show that attenuation coefficients of sample A and B at the fundamental frequency stay constant and slightly increase at the second harmonic at the PNP below 100kPa, indicating a linear oscillation of MBs. As the PNP reaches 200kPa, the attenuation coefficient of sample A at fundamental frequency decreases while at 2nd and 3rd harmonics increases, indicating that the energy of the echo shifts from the fundamental frequency to the 2nd and 3rd harmonics. As the PNP goes higher to 300kPa, the attenuation coefficient of sample A at the fundamental frequency, 2nd, and 3rd harmonics decreases, suggesting that the energy shifts to an even higher harmonic. At the same time, the attenuation coefficient of sample B stays constant at fundamental frequency, decreases at 2nd harmonics, and increases at the 3rd harmonic, suggesting the energy starts to shift to the 3rd harmonic. The attenuation coefficient of sample C at fundamental frequency, 2nd and 3rd harmonics keep constant and low due to low sample concentration. The test reveals the energy shifting of the echo to the higher harmonics at PNP higher than 100 kPa, indicating the nonlinear oscillation of MBs at PNP higher than 100 kPa. Moreover, the concentration of the MBs seems to influence the energy shifting: the higher the concentration the earlier the shift to the higher harmonics occurs, in the range of the concentration consider in this study.

    The pilot results of the micro-CT tests are presented in Table 1. The reference, gold nanoparticles solution, has the highest CNR per voxel at all CT operating voltages. The CNR per voxel of CACTUS MBs suspensions is below 0.1, virtually equaling the MBs at all operating voltages, suggesting that no gold or very little gold were loaded into the shell of the CACTUS MBs. The gold loaded capsules suspension has higher CNR per voxel than the capsule supernatant (the surrounding environment of capsules) and the MBs suspension, implying that the gold nanoparticles were loaded into the capsules. However, it is not clear whether the gold nanoparticles were loaded in the core of the MBs or in the MBs shell. The expected sharp increase of CNR per voxel at the k-edge of gold did not appear. We believe that is because even at our highest operating voltage of 90kV, the percentage of the photons with energy higher than 80.7 keV is still low. Introduction of a high-pass metal filter could increase the percentage of high energy photon. On the other hand, the metal filter will reduce the total number of the photons which would increase the noise of the images. Since same current was applied on every CT test, less X-ray photons reached the sensors when the CT was operated at low voltage. Therefore, it might be worth performing additional calibration tests to adjust the operating currents to make sure that the numbers of the photons that reach the sensor at every operating voltage are the same.

    Conclusion

    In this study, the CACTUS MBs and gold loaded capsules were fabricated as potential candidates for dual modal contrast agent. The characterization revealed that gold loaded capsule is a promising initial step. Nevertheless, the method to convert back liquid-core capsules to gas-core MBs needs to be established.

    [1] Cavalieri, F., El Hamassi, A., Chiessi, E., Paradossi, G., Villa, R., & Zaffaroni, N. (2006). Tethering functional ligands onto shell of ultrasound active polymeric microbubbles. Biomacromolecules, 7(2), 604-611.

  • 10.
    Chen, Hongjian
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Löffler, Wendi
    KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Information Science and Engineering.
    Grishenkov, Dmitry
    Model-guided customization of a contrast pulse sequence for polyvinyl alcohol microbubblesManuscript (preprint) (Other academic)
    Abstract [en]

    Simulations of microbubbles (MBs) suggest that the excitation threshold for sub-harmonic generation is frequency-dependent. The minimum threshold, dependent on models and assumptions, might appear near the resonance frequency. Given that, in the current study, attempts were made to optimize a novel contrast pulse sequence, CPS4, for the in-house ultrasound contrast agent, polyvinyl alcohol microbubbles (PVA MBs) by setting the transmitting frequency near their resonance frequency to boost the sub-harmonic response. An improved model for PVA MBs was proposed to predict the resonance frequency. An in-vitro experiment was performed to evaluate the performance of CPS4 at different transmitting frequencies. The experiment results suggest the optimal performance of CPS4 with PVA MBs aqueous suspension appeared at the transmitting frequency of 11.25 MHz, which agrees with the values of the damped resonance frequency determined from simulation. The influence of the liquid environment on the performance of the CPS4 was also studied. The replacement of water with artificial blood degrades the contrast-to tissue ratio of CPS4 and shifts the optimal performance to the higher transmitting frequency.

  • 11.
    Chen, Hongjian
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Löffler, Wendi
    KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Information Science and Engineering.
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Sequence design for ultrasound imaging of polyvinyl alcohol microbubbles2020Conference paper (Refereed)
    Abstract [en]

    In the previous study [1], a novel contrast pulse sequence, CPS4, was introduced. The CPS4 combined sub-harmonic, ultra-harmonic and pulse inverse imaging to provide an improved contrast-to-tissue ratio (CTR). The CPS4 emits two pairs of transmitting waves at frequencies of f0/2 and 2*f0 with inversed phase within each pair and filters the received echoes at the frequency of f0. However, the performance of CPS4 was not optimized. Simulation study [2] shows that there is a pressure threshold for the sub-harmonic response generation of the ultrasound contrast agent (UCA). The threshold is expected to reach its local minima with the transmitting frequency around the resonance frequency. By lowering the threshold, more MBs could be excited to response sub-harmonic signal which could improve the CTR of CPS4.

    The current study aims to investigate frequency-dependent performance of CPS4 with the polyvinyl alcohol microbubbles (PVA MBs). First a linear oscillator model adapted from Hoff and Church[3, 4] was built for single PVA MB. The attenuation and phase velocity of a PVA MB suspension were obtained to calibrate the linear oscillator. The model was used to estimate the resonance frequency of the MBs. The transmitting frequency of CPS4 for sub-harmonic was set at four frequency points around the local minima, i.e. resonance frequency. The performance of CPS4 at different frequencies were evaluated.

  • 12.
    Chen, Hongjian
    et al.
    Department of Clinical Sciences, Intervention and Technology, Karolinska Institute, Stockholm, Sweden.
    Zhao, Ying
    Division of Experimental Cancer Medicine, Department of Laboratory Medicine (LABMED), Karolinska Institute,.
    Grishenkov, Dmitry
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging. Department of Clinical Sciences, Intervention and Technology, Karolinska Institute, Stockholm, Sweden.
    Polymer microbubbles loaded with gold nanoparticles as hybrid contrast agent for computed tomography and ultrasound2020In: Biomedical Research and Clinical Practice, ISSN 2397-9631, Vol. 5, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Microbubbles (MBs) with size below 10 μm are commonly used as an ultrasound contrast agent (UCA). The aim of the novel UCA developed in our lab is to support imaging modalities other than ultrasound to form hybrid contrast agents. The hybrid contrast agents through the synergistic effect can potentially improve the diagnostic outcome of the combined multimodal imaging technique. In this study, we modified the polyvinyl alcohol (PVA) MB fabrication protocol to encapsulate the gold nanoparticles into the shell and also in the core of the MBs. Furthermore, we evaluated the morphology, nonlinear ultrasound response, and X-ray property of dual modal contrast agents. The results revealed that the loading of the gold nanoparticles into the PVA MB core is a promising step towards the development of the dual modal contrast agent.

  • 13.
    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.

  • 14.
    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.

  • 15.
    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.

  • 16.
    Ghorbani, Morteza
    et al.
    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, 34956 Tuzla, Istanbul, Turkey.
    Araz, Sheybani Aghdam
    Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul 34956, Turkey.
    Talebian, Moein
    Mechatronics Engineering Program, Faculty of Engineering and Natural Science, Sabanci University, 34956 Tuzla, Istanbul, Turkey.
    Kosar, Ali
    Mechatronics Engineering Program, Faculty of Engineering and Natural Science, Sabanci University, 34956 Tuzla, Istanbul, Turkey ; Sabanci University Nanotechnology Research and Application Center, 34956 Tuzla, Istanbul, Turkey ; Center of Excellence for Functional Surfaces and Interfaces for Nano-Diagnostics (EFSUN), Sabanci University, Orhanli, 34956 Tuzla, Istanbul, Turkey.
    Cakmak Cebeci, Fevzi
    Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul 34956, Turkey ; Sabanci University Nanotechnology Research and Application Center, 34956 Tuzla, Istanbul, Turkey.
    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 Surfaces2019In: Chemical Engineering Journal, ISSN 1385-8947, E-ISSN 1873-3212Article in journal (Refereed)
    Abstract [en]

    The tremendous potential of “hydrodynamic cavitation on microchips” has been highlighted during recent years in various applications. Cavitating flow patterns, substantially depending upon thermophysical and geometrical characteristics, promote diverse industrial and engineering applications, including food and biomedical treatment. Highly vaporous and fully developed patterns in microfluidic devices are of particular interest. In this study, the potential of a new approach, which includes cellulose nanofiber (CNF)- stabilized perfluorodroplets (PFC5s), was assessed inside microfluidic devices. The surfaces of these devices were modified by assembling various sizes of silica nanoparticles, which facilitated in the generation of cavitation bubbles. To examine the pressure effects on the stabilized droplets in the microfluidic devices, the upstream pressure was varied, and the cavitation phenomenon was characterized under different experimental conditions. The results illustrate generation of interesting, fully developed, cavitating flows at low pressures for the stabilized droplets, which has not been previously observed in the literature. Supercavitation flow pattern, filling the entire microchannel, were recorded at the upstream pressure of 1.7 MPa for the case of CNF-stabilized PFC5s, which hardly corresponds to cavitation inception for pure water in the same microfluidic device.

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  • 17. 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, ISSN 1070-6631, E-ISSN 1089-7666, 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.

  • 18.
    Ghorbani, Morteza
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging. Sabanci Univ, Fac Engn & Nat Sci, Mechatron Engn Program, TR-34956 Istanbul, Turkey.
    Olofsson, Karl
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Benjamins, Jan-Willem
    Research Institute of Sweden (RISE), Chemistry, Materials and Surfaces, Box 5607, SE-114 86 Stockholm, Sweden.
    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 Nanofibers2019In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 35, no 40, p. 13090-13099Article in journal (Refereed)
    Abstract [en]

    The attractive colloidal and physicochemical properties of cellulose nanofibers (CNFs) at interfaces have recently been exploited in the facile production of a number of environmentally benign materials, e.g. foams, emulsions, and capsules. Herein, these unique properties are exploited in a new type of CNF-stabilized perfluoropentane droplets produced via a straightforward and simple mixing protocol. Droplets with a comparatively narrow size distribution (ca. 1–5 μm in diameter) were fabricated, and their potential in the acoustic droplet vaporization process was evaluated. For this, the particle-stabilized droplets were assessed in three independent experimental examinations, namely temperature, acoustic, and ultrasonic standing wave tests. During the acoustic droplet vaporization (ADV) process, droplets were converted to gas-filled microbubbles, offering enhanced visualization by ultrasound. The acoustic pressure threshold of about 0.62 MPa was identified for the cellulose-stabilized droplets. A phase transition temperature of about 22 °C was observed, at which a significant fraction of larger droplets (above ca. 3 μm in diameter) were converted into bubbles, whereas a large part of the population of smaller droplets were stable up to higher temperatures (temperatures up to 45 °C tested). Moreover, under ultrasound standing wave conditions, droplets were relocated to antinodes demonstrating the behavior associated with the negative contrast particles. The combined results make the CNF-stabilized droplets interesting in cell-droplet interaction experiments and ultrasound imaging.

  • 19.
    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. 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).

     

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  • 20.
    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.
    Targeted Hydrodynamic Cavitating Flows via Ultrasound Waves via Pickering Stabilized Perfluorodroplets2020Conference paper (Refereed)
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  • 21.
    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)
  • 22.
    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.

     

  • 23.
    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.

  • 24.
    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.

  • 25.
    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.

  • 26.
    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, 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.

  • 27.
    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.

  • 28.
    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.

  • 29.
    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.

  • 30.
    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.

  • 31.
    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.

  • 32.
    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.

  • 33.
    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.

  • 34.
    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.

  • 35.
    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.

  • 36.
    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.

  • 37.
    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)
  • 38.
    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).

  • 39.
    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.

  • 40.
    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.

  • 41.
    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.

  • 42.
    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)
  • 43.
    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.

  • 44.
    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. 

  • 45.
    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)
  • 46.
    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.

  • 47.
    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)
  • 48.
    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.

    Download full text (pdf)
    fulltext
  • 49.
    Loskutova, Ksenia
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Nimander, Didrik
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH).
    Gouwy, Isabelle
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH).
    Chen, Hongjian
    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.
    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).
    A Study on the Acoustic Response of Pickering Perfluoropentane Droplets in Different Media2021In: ACS Omega, E-ISSN 2470-1343Article in journal (Refereed)
    Abstract [en]

    Acoustic droplet vaporization (ADV) is the physical process of liquid-to-gas phase transition mediated by pressure variations in an ultrasound field. In this study, the acoustic response of novel particle-stabilized perfluoropentane droplets was studied in bulk and confined media. The oil/water interface was stabilized by cellulose nanofibers. First, their acoustic responses under idealized conditions were examined to assess their susceptibility to undergo ADV. Second, the droplets were studied in a more realistic setting and placed in a confined medium. Lastly, an imaging setup was developed and tested on the droplets. The acoustic response could be seen when the amplitude of the peak negative pressure (PNP) was above 200 kPa, suggesting that this is the vaporization pressure threshold for these droplets. Increasing the PNP resulted in a decrease in signal intensity over time, suggesting a more destructive behavior. The imaging setup was able to differentiate between the droplets and the surrounding tissue. Results obtained within this study suggest that these droplets have potential in terms of ultrasound-mediated diagnostics and therapy.

    Download full text (pdf)
    article
  • 50.
    Loskutova, Ksenia
    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.
    Hammarström, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Svagan, Anna Justina
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology.
    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.
    Assessment of the Mechanical Propertiesof Cellulose Nanofiber-Stabilized Droplets Using Acoustophoresis2021Conference paper (Refereed)
    Abstract [en]

    In this work, the compressibility of Pickering-stabilized perfluoropentane droplets was determined by using acoustophoresis. Polyamide beads with known density, size and compressibility were used to calculate the pressure amplitude inside the microchannel. The results show that the compressibility of CNF-stabilized droplets is significantly higher than for water, but lower than for pure PFC5. This shows promising potential for these droplets to be used in ultrasound-mediated clinical applications. It has also been shown that acoustophoresis can successfully measure the compressibility of pressure-sensitive particles for small USW pressure amplitudes. As the droplets relocate to pressure anti-nodes just as gas-filled microbubbles, it would be possible to study cell-droplet and cell-gasbubble in the same  setup.

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