Influence of injection site, microvascular pressureand ultrasound variables on microbubble-mediated delivery of microspheres to muscle

Song, Ji Sun; Chappell, John C.; Qi, Ming; VanGieson, Eric J; Kaul, Sanjiv; Price, Richard J.

doi:10.1016/s0735-1097(01)01793-4

Cited by 111 publications

(82 citation statements)

References 13 publications

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“…Likewise a collapse of a microbubble near a capillary or blood vessel wall will cause the liquid jet to shoot right into the wall. Such a collapse may be the source of the large amount of extravasation that is caused in tissue exposed to ultrasound in the presence of microbubble contrast agents [32][33][34][35]. There is some concern that a blood vessel injury by sonic jets, shear stresses, or radicals could generate a nidus for thrombus formation.…”

Section: Cell Permeabilization and Capillary Rupturementioning

confidence: 99%

Ultrasonic drug delivery – a general review

Pitt

Husseini

Staples

2004

Expert Opinion on Drug Delivery

557

448

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Ultrasound (US) has an ever-increasing role in the delivery of therapeutic agents including genetic material, proteins, and chemotherapeutic agents. Cavitating gas bodies such as microbubbles are the mediators through which the energy of relatively non-interactive pressure waves is concentrated to produce forces that permeabilize cell membranes and disrupt the vesicles that carry drugs. Thus the presence of microbubbles enormously enhances delivery of genetic material, proteins and smaller chemical agents. Delivery of genetic material is greatly enhanced by ultrasound in the presence of microbubbles. Attaching the DNA directly to the microbubbles or to gas-containing liposomes enhances gene uptake even further. US-enhanced gene delivery has been studied in various tissues including cardiac, vascular, skeletal muscle, tumor and even fetal tissue. US-enhanced delivery of proteins has found most application in transdermal delivery of insulin. Cavitation events reversibly disrupt the structure of the stratus corneum to allow transport of these large molecules. Other hormones and small proteins could also be delivered transdermally. Small chemotherapeutic molecules are delivered in research settings from micelles and liposomes exposed to ultrasound. Cavitation appears to play two roles: it disrupts the structure of the carrier vesicle and releases the drug; it also makes the cell membranes and capillaries more permeable to drugs. There remains a need to better understand the physics of cavitation of microbubbles and the impact that such cavitation has upon cells and drug-carrying vesicles.

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Section: Cell Permeabilization and Capillary Rupturementioning

confidence: 99%

Ultrasonic drug delivery – a general review

Pitt

Husseini

Staples

2004

Expert Opinion on Drug Delivery

557

448

View full text Add to dashboard Cite

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“…The change in capillary permeability is strongly dependent on bubble size and concentration, and acoustic pressure and frequency. With a sufficiently high microbubble concentration, ultrasonic pressure on the order of 0.75 MPa at a center frequency of 1 MHz can produce capillary rupture in the intact rat muscle microcirculation; and the pressure required increases with increasing ultrasound frequency [11,12]. Direct visualization of microbubble-vessel interaction has been reported [13], where the expansion of the microbubble within small vessels was decreased, the lifetime of the microbubble increased, and larger microbubbles were shown to directly contact the wall.…”

Section: Changes In Tissue/vascular Transport Propertiesmentioning

confidence: 99%

Driving delivery vehicles with ultrasound

Ferrara

2008

Advanced Drug Delivery Reviews

231

162

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Therapeutic applications of ultrasound have been considered for over 40 years, with the mild hyperthermia and associated increases in perfusion produced by ultrasound harnessed in many of the earliest treatments. More recently, new mechanisms for ultrasound-based or ultrasound-enhanced therapies have been described, and there is now great momentum and enthusiasm for the clinical translation of these techniques. This dedicated issue of Advanced Drug Delivery Reviews, entitled "Ultrasound for Drug and Gene Delivery," addresses the mechanisms by which ultrasound can enhance local drug and gene delivery and the applications that have been demonstrated at this time. In this commentary, the identified mechanisms, delivery vehicles, applications and current bottlenecks for translation of these techniques are summarized. KeywordsUltrasound; Therapy; Drug delivery; Gene delivery; Sonoporation; Cavitation As an imaging modality, ultrasound is widely employed and valued for its real time applications, low cost, simplicity, and safety. Waves of alternating increased and decreased pressure propagate from the transducer, typically resulting in a maximum intensity in a focal region chosen by the operator. The dimensions of the focal region can vary from tens of microns for high frequency ultrasound to centimeters for an unfocused therapeutic beam. Most clinical instruments are engineered to effectively image from the body surface to 24 or more centimeters in depth. The ability to locally control and maximize energy deposition deep within the body facilitates a broad range of clinical opportunities for ultrasound imaging and therapy. Developing over four decades, clinical and commercial application of ultrasonic therapies spans hyperthermia, drug delivery, lipoplasty, and thrombolysis [1,2]. A complete and precise summary of the potential applications for ultrasonic enhancement of drug and gene delivery remains challenging as the mechanisms are multiple and not fully characterized. From an engineering viewpoint, the methods by which ultrasound facilitates drug and gene delivery can be summarized as direct changes in the biological or physiological properties of tissues facilitating transport, direct changes in the drug or vehicle increasing bioavailability or enhancing efficacy, and indirect effects by which ultrasound acts on the vehicle to produce changes in the surrounding tissue. While there are common mechanisms between these methods, the engineering challenges associated with the optimization of ultrasound systems and drug and vehicle design are unique for each method. Promising examples of each of these methods can be identified at this time and are addressed below.☆ This commentary is part of the Advanced Drug Delivery Reviews theme issue on "Ultrasound in Drug and Gene Delivery".

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“…Previously, vascular rupture due to bubble activity was observed and reported in different studies. 4,5,[16][17][18] A numerical simulation of the experimental data could shed light on understanding bubble-vessel interactions. In particular, such a theoretical model could predict encapsulated bubble oscillations inside a vessel.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of microbubble–vessel interactions and induced stresses: A numerical study

Hosseinkhah

Chen

Matula

et al. 2013

The Journal of the Acoustical Society of America

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Oscillating microbubbles within microvessels could induce stresses that lead to bioeffects or vascular damage. Previous work has attributed vascular damage to the vessel expansion or bubble jet. However, ultra-high speed images of recent studies suggest that it could happen due to the vascular invagination. Numerical simulations of confined bubbles could provide insight into understanding the mechanism behind bubble-vessel interactions. In this study, a finite element model of a coupled bubble/fluid/vessel system was developed and validated with experimental data. Also, for a more realistic study viscoelastic properties of microvessels were assessed and incorporated into this comprehensive numerical model. The wall shear stress (WSS) and circumferential stress (CS), metrics of vascular damage, were calculated from these simulations. Resultant amplitudes of oscillation were within 15% of those measured in experiments (four cases). Among the experimental cases, it was numerically found that maximum WSS values were between 1.1-18.3 kPa during bubble expansion and 1.5-74 kPa during bubble collapse. CS was between 0.43-2.2 MPa during expansion and 0.44-6 MPa while invaginated. This finding confirmed that vascular damage could occur during vascular invaginations. Predicted thresholds in which these stresses are higher during vessel invagination were calculated from simulations.

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Influence of injection site, microvascular pressureand ultrasound variables on microbubble-mediated delivery of microspheres to muscle

Abstract: The ultrasound PI and microvascular pressure significantly influence the creation of extravasation points and the transport of microspheres to tissue. These factors may be important in designing and optimizing contrast ultrasound-based therapies.

Cited by 111 publications

References 13 publications

Ultrasonic drug delivery – a general review

Ultrasonic drug delivery – a general review

Driving delivery vehicles with ultrasound

Mechanisms of microbubble–vessel interactions and induced stresses: A numerical study

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