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Intensifying cavitating flows in microfluidic devices with poly(vinyl alcohol) (PVA) microbubbles
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems.
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging. (Contrast Enhanced Medical Imaging and Therapy)ORCID iD: 0000-0002-3699-396X
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2018 (English)In: Physics of fluids, ISSN 1070-6631, E-ISSN 1089-7666, Vol. 30, no 10Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Institute of Physics (AIP), 2018. Vol. 30, no 10
National Category
Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
URN: urn:nbn:se:kth:diva-236312DOI: 10.1063/1.5051606ISI: 000448975800005Scopus ID: 2-s2.0-85055129019OAI: oai:DiVA.org:kth-236312DiVA, id: diva2:1256417
Note

QC 20220412

Available from: 2018-10-16 Created: 2018-10-16 Last updated: 2024-03-15Bibliographically approved
In thesis
1. Exploring Polymer-Shelled Microbubbles: Detection Modeling and Application
Open this publication in new window or tab >>Exploring Polymer-Shelled Microbubbles: Detection Modeling and Application
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ultrasound imaging (US) is widely used in clinical practice. Given the low cost and easy access to the ultrasound machine, US has a great potential to improve the health care condition for the majority of the population in the world. The US could be significantly improved by injecting ultrasound contrast agents to opacify the bloodstream. The polymer-shelled microbubbles (MB) are promising candidates for the next generation ultrasound contrast agent. In the current doctoral work, one of the polymer-shelled MBs, the polyvinyl alcohol (PVA) MB was investigated.

In Study I and Study II, I developed a novel contrast pulse sequence, CPS4, to efficiently detect the PVA MBs. The CPS4 is a combination of the sub-harmonic (SH), ultra-harmonic, and pulse inversion techniques. The comparison of the performance of each individual technique and CPS4 was carried out in a tissue-mimicking phantom. The CPS4 demonstrated the highest contrast-to-tissue ratio among all four imaging techniques. However, the SH response of the CPS4 was not fully excited. The high SH pressure threshold, above which the SH response is generated, was suspected to be the reason for the weak SH signal. Therefore, I wanted to optimize the performance of the CPS4 for the PVA MBs detection by boosting the SH signal. The optimization strategy was to lower the frequency-dependent SH threshold by setting the SH excitation frequency, which is the frequency of the ultrasound wave that excites the SH response, at the damped resonance frequency of the PVA MBs. To estimate the damped resonance frequency, a mathematical model based on the Church’s model with frequency-dependent material properties was proposed. The mechanical parameters of the new model were estimated by fitting the measured attenuation coefficient of the PVA MBs suspension with the simulated one. The calibrated model was employed to predict the damped resonance frequency of the PVA MBs, i.e., the optimized SH excitation frequency for the CPS4. The performance of the CPS4 was evaluated in-vitro, driving the system at four SH excitation frequencies in the proximity of the damped resonance frequency of the PVA MBs suspension. The best performance was observed at the SH excitation frequency of 11.25 MHz, which is in line with the simulated damped resonance frequency of 10.85 MHz. The in vitro experiment also revealed that the small particles constituting the artificial blood solution might interact with the PVA MBs and decreased the response echoes in a nonlinear and frequency-dependent fashion. Thus, more efforts are needed to move our model-guided optimization methods for the CPS4 towards clinical application.

In Study III, I modified the PVA MBs to support the dual-modal imaging of CT and US. The main idea of the modification is to incorporate the gold nanoparticles with the PVA MBs. The success of the modification is dependent on the amount of the gold nanoparticles carried by the modified PVA MBs. Two routes were proposed to fabricate candidates that support dual-modal imaging. In the first route, the gold nanoparticles were added during the fabrication of PVA MBs. Thus, the gold nanoparticles were embedded in the PVA shell during its formation (candidate named AuNP-S-MB). In the second route, the gold nanoparticles were loaded into the core of the PVA MBs, substituting air by increasing the permeability (candidate named AuNP-Capsule). The CT revealed an insignificant amount of gold nanoparticles was embedded in the shell of AuNP-S-MB, while detectable gold nanoparticles were loaded into AuNP-Capsule. Moreover, the CT-number of the surrounding liquid of AuNP-Capsule is low, i.e., the gold nanoparticles were locked in the AuNP-Capsule, making the second route a promising step towards the further development of the dual-modal contrast agent for CT and US.

In Study IV, I studied the effect of PVA MBs on the cavitation flows in microscale. The cavitation in clinical practices generates great pressure, which might be harmful and damage cells or beneficial and facilitate the treatment. A better understanding of cavitation generation mechanisms could avoid harmful cavitation, increase the safety of the clinical protocol, and increase the therapeutic cavitation, empower the treatments. Therefore, the effect of PVA MBs on cavitation is of great interest. More specifically, the effect of PVA MBs on the hydrodynamic cavitation was studied. Three microfluidic devices with different wall roughness and structure were fabricated. Two working fluids, PVA MBs suspension and water, were driven with controlled pressure through different microfluidic devices. The high-speed visualization revealed that the PVA MBs trigger the inception of hydrodynamic cavitation at a lower upstream pressure and enhance the cavitation flow in all three microfluidic devices. Furthermore, it takes a longer time for the cavitation bubbles to disappear in the PVA MB suspension.

To conclude the doctoral work, I developed a novel detection sequence, CPS4, optimized it for PVA MBs with a model-guided method, modified the PVA MB to extend its application, and studied the effect of PVA MB on hydrodynamic cavitation. The work promotes the PVA MBs for pre-clinical study, as well as provides an insight into the studies of other clinically approved ultrasound contrast agents. The methodology developed and presented within the thesis can be transferred to other clinically approved ultrasound contrast agents. For instance, the CPS4 and model-guided optimization method could be employed to improve CPS4 to other ultrasound contrast agents.

Abstract [sv]

Ultraljudsavbildning (US) används ofta inom klinisk praxis. Med tanke påultraljudsmaskinens låga kostnad och enkla åtkomst har den förbättrade US en stor potentialför att förbättra hälsovården för majoriteten av världsbefolkningen. US kan förbättrasavsevärt genom att injicera ultraljudskontrastmedel för att göra blodflödet opakt.Mikrobubblor (MB) med polymerskal är lovande kandidater för nästa generationsultraljudskontrastmedel. I det aktuella doktorandprojektet undersöktes MB med en viss typav polymerskal, polyvinylalkohol (PVA) MB.

I Studie I och II utvecklade jag en ny kontrastpulssekvens, CPS4, för att effektivt detekteraPVA MB. CPS4 är en kombination av subharmoniska (SH), ultraharmoniska ochpulsinverteringstekniker. Jämförelsen av prestandan för varje enskild teknik och CPS4utfördes i en vävnadsfantom. CPS4 visade det högsta förhållandet mellan kontrast ochvävnad av alla fyra avbildningstekniker. SH- svar i CPS4 var dock inte helt exciterad. Dethöga SH-tröskelvärdet, över vilket ett SH-svar genereras, var misstänkt för att vara orsakentill den svaga SH-signalen. Därför ville jag optimera prestandan för CPS4 för detektering avPVA MB genom att öka SH-signalen. Optimeringsstrategin var att sänka detfrekvensberoende SH-tröskelvärdet genom att ställa in sändningsfrekvensen för CPS4, somär frekvensen hos den ultraljudsvåg som exciterar SH-svaret, vid den dämpaderesonansfrekvensen för PVA MB. För att uppskatta den dämpade resonansfrekvensenföreslogs en matematisk modell baserad på Churchs modell med frekvensberoendematerialegenskaper. De mekaniska parametrarna i den nya modellen estimerades genom attanpassa den uppmätta dämpningskoefficienten för PVA MB-suspensionen med densimulerade. Den kalibrerade modellen användes för att förutspå den dämpaderesonansfrekvensen för PVA MB, dvs. den optimerade SH-frekvensen för CPS4. CPS4-algoritmens prestanda utvärderades in vitro genom att köra systemet vid fyra olika frekvensersom ligger i närheten av den dämpade PVA MB-resonansfrekvensen. Den bästa prestandanobserverades vid 11.25 MHz, vilket är i linje med den simulerade dämpaderesonansfrekvensen på 10.85 MHz. In vitro-experimentet avslöjade också att de småpartiklarna som utgör den konstgjorda blodfantomen kan interagera med PVA MB ochminskade svarsekon på ett icke-linjärt och frekvensberoende sätt. Således behövs fler studierför att våra modellstyrda optimeringsmetoder för att CPS4 ska kunna tillämpas kliniskt.

I Studie III modifierade jag PVA MB:na för att stödja dubbelmodal avbildning för CT ochUS. Huvudidén med modifieringen är att införliva guldnanopartiklar i PVA MB. Huruvidamodifieringen är framgångsrik beror på storleken på nyttolasten som bärs av PVA MB. Tvåolika tillvägagångssätt föreslogs för att tillverka kandidater som stöder dubbelmodalavbildning. I det första tillvägagångssättet tillsattes guldnanopartiklarna under tillverkningenav PVA MB, så att guldnanopartiklarna bäddades in i PVA-skalet under dess bildande(kandidat som heter AuNP-S-MB). I det andra tillvägagångssättet laddadesguldnanopartiklarna in i kärnan i PVA MB som ersatte luft genom att öka permeabiliteten(kandidat som heter AuNP-kapsel). CT avslöjade att en obetydlig mängd guldnanopartiklarvar inbäddade i skalet av AuNP-S-MB, medan en detekterbar mängd guldnanopartiklarpackades in i PVA MB. Dessutom är CT-numret för den omgivande vätskan kring AuNPkapseln lågt, dvs. guldnanopartiklarna var bundna inuti AuNP-kapseln, vilket gör det andratillvägagångssättet till ett lovande steg mot den vidare utvecklingen av dubbelmodaltkontrastmedel.

I Studie IV studerade jag effekten av PVA MB på kavitationsflöden i mikroskala.Kavitationen i klinisk praxis genererar stora tryck, vilket kan vara ogynnsamt och skada cellereller vara till nytta och underlätta en behandling. En bättre förståelse för mekanismen förkavitationsgenerering kan undvika skadlig kavitation, öka säkerheten för det kliniskaprotokollet och öka den terapeutiska kavitationen. Därför är effekten av PVA MB påkavitationen av stort intresse. Mer specifikt studerades effekten av PVA MB på denhydrodynamiska kavitationen. Tre mikrofluidanordningar med olika strukturer ochytjämnheter på väggarna tillverkades. Två arbetsvätskor, PVA MB-suspension och vatten,kördes med kontrollerat tryck genom de olika mikrofluidanordningarna.Höghastighetsvisualiseringen avslöjade att PVA MB:na utlöser starten av hydrodynamiskkavitation vid ett lägre tryck uppströms och förbättrar kavitationsflödet i alla tremikrofluidanordningarna. Dessutom tar det längre tid för kavitationsbubblorna att försvinnai PVA MB-suspensionen.

För att sammanfatta mitt doktorandarbete har jag utvecklat en ny detektionssekvens, CPS4,optimerat den för PVA MB med en modellstyrd metod, modifierat PVA MB för att utvidgadess tillämpning, och studerat effekten av PVA MB på hydrodynamisk kavitation. Arbetetfrämjar PVA MB för prekliniska studier, samt ger en inblick i studierna av de andra klinisktgodkända ultraljudskontrastmedlen. Metoderna som utvecklats och presenterats inomavhandlingen kan tillämpas på andra kliniskt godkända ultraljudskontrastmedel. Till exempelkan CPS4 och modellstyrd optimeringsmetod användas för att detektera andraultraljudskontrastmedel med hög effektivitet, vilket erbjuder en överlägsen upplösning.

Place, publisher, year, edition, pages
Stockholm, Sweden: KTH Royal Institute of Technology, 2020. p. 51
Series
TRITA-CBH-FOU ; 2020:56
Keywords
Ultrasound contrast agent, polymer-shelled microbubble, ultrasound imaging, contrast pulse sequence, microbubble model, hydrodynamic cavitation
National Category
Radiology, Nuclear Medicine and Medical Imaging
Research subject
Technology and Health
Identifiers
urn:nbn:se:kth:diva-286056 (URN)978-91-7873-712-3 (ISBN)
Public defence
2020-12-11, https://kth-se.zoom.us/webinar/register/WN_xhQ7-iQIQya3g89SOlLR4w, 09:00 (English)
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Note

QC 2020-11-18

Available from: 2020-11-18 Created: 2020-11-18 Last updated: 2022-06-25Bibliographically approved

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Chen, HongjianGrishenkov, Dmitry

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