This article reviews acoustic microfiuidics: the use of acoustic fields, principally ultrasonics, for application in microfiuidics. Although acoustics is a classical field, its promising, and indeed perplexing, capabilities in powerfully manipulating both fluids and particles within those fluids on the microscale to nanoscale has revived interest in it. The bewildering state of the literature and ample jargon from decades of research is reorganized and presented in the context of models derived from first principles. This hopefully will make the area accessible for researchers with experience in materials science, fluid mechanics, or dynamics. The abundance of interesting phenomena arising from nonlinear interactions in ultrasound that easily appear at these small scales is considered, especially in surface acoustic wave devices that are simple to fabricate with planar lithography techniques common in microfluidics, along with the many applications in microfluidics and nanofluidics that appear through the literature.

/pdf/microscale-acoustofluidics-microfluidics-driven-via-5bet39j13p.pdf

Microscale acoustofluidics: Microfluidics driven via acoustics and ultrasonics

Artificial nano/microscale machines hold great promise for diverse future biomedical applications. This Perspective summarizes recent advances in microscale motors, as exemplified by Hoyos and Mallouk in this issue of ACS Nano, and highlights the challenges and opportunities in translating this remarkable progress toward practical biomedical applications. Various areas of medicine, including targeted drug delivery, precision nanosurgery, biopsy, cell sorting, or diagnostic assays, would benefit from recent developments of efficient fuel-free and fuel-driven nano/microscale machines. Newly introduced ultrasound-driven propulsion mechanisms greatly enhance the prospects for these biomedical applications. With continuous innovation and attention to key challenges, we expect that man-made nano/microscale motors will have profound impact upon different medical areas.

Nano/Microscale motors: biomedical opportunities and challenges.

Advantages and Challenges of Relaxor-PbTiO3 Ferroelectric Crystals for Electroacoustic Transducers- A Review.

Applications of ultrasound in medicine for therapeutic purposes have been accepted and beneficial uses of ultrasonic biological effects for many years. Low-power ultrasound of about 1 MHz has been widely applied since the 1950s for physical therapy in conditions such as tendinitis and bursitis. In the 1980s, high-pressure-amplitude shock waves came into use for mechanically resolving kidney stones, and "lithotripsy" rapidly replaced surgery as the most frequent treatment choice. The use of ultrasonic energy for therapy continues to expand, and approved applications now include uterine fibroid ablation, cataract removal (phacoemulsification), surgical tissue cutting and hemostasis, transdermal drug delivery, and bone fracture healing, among others. Undesirable bioeffects can occur, including burns from thermal-based therapies and severe hemorrhage from mechanical-based therapies (eg, lithotripsy). In all of these therapeutic applications of ultrasound bioeffects, standardization, ultrasound dosimetry, benefits assurance, and side-effect risk minimization must be carefully considered to ensure an optimal benefit to risk ratio for the patient. Therapeutic ultrasound typically has well-defined benefits and risks and therefore presents a manageable safety problem to the clinician. However, safety information can be scattered, confusing, or subject to commercial conflicts of interest. Of paramount importance for managing this problem is the communication of practical safety information by authoritative groups, such as the American Institute of Ultrasound in Medicine, to the medical ultrasound community. In this overview, the Bioeffects Committee of the American Institute of Ultrasound in Medicine outlines the wide range of therapeutic ultrasound methods, which are in clinical use or under study, and provides general guidance for ensuring therapeutic ultrasound safety.

Overview of Therapeutic Ultrasound Applications and Safety Considerations

Recent advances in high intensity focused ultrasound (HIFU), which was developed in the 1940s as a viable thermal tissue ablation approach, have increased its popularity. In clinics, HIFU has been applied to treat a variety of solid malignant tumors in a well-defined volume, including the pancreas, liver, prostate, breast, uterine fibroids, and soft-tissue sarcomas. In comparison to conventional tumor/cancer treatment modalities, such as open surgery, radio- and chemo-therapy, HIFU has the advantages of non-invasion, non-ionization, and fewer complications after treatment. Over 100 000 cases have been treated throughout the world with great success. The fundamental principles of HIFU ablation are coagulative thermal necrosis due to the absorption of ultrasound energy during transmission in tissue and the induced cavitation damage. This paper reviews the clinical outcomes of HIFU ablation for applicable cancers, and then summarizes the recommendations for a satisfactory HIFU treatment according to clinical experience. In addition, the current challenges in HIFU for engineers and physicians are also included. More recent horizons have broadened the application of HIFU in tumor treatment, such as HIFU-mediated drug delivery, vessel occlusion, and soft tissue erosion (“histotripsy”). In summary, HIFU is likely to play a significant role in the future oncology practice.

High intensity focused ultrasound in clinical tumor ablation

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.

/pdf/ultrasonic-drug-delivery-a-general-review-53bn9zfyxj.pdf

Ultrasonic Drug Delivery – A General Review

Distribution of Doxorubicin in Rats Undergoing Ultrasonic Drug Delivery

Purpose
The therapeutic effect of ultrasound and micellar-encapsulated doxorubicin was studied in vivo using a tumor-bearing rat model with emphasis on how tumor growth rate is affected by ultrasonic parameters such as frequency and intensity.

/pdf/role-of-frequency-and-mechanical-index-in-ultrasonic-3cyvyj3d2w.pdf

Role of frequency and mechanical index in ultrasonic-enhanced chemotherapy in rats

PHARMACOKINETICS OF ULTRASONICALLY-RELEASED, MICELLE ENCAPSULATED DOXORUBICIN IN THE RAT MODEL AND ITS EFFECT ON TUMOR GROWTH Bryant J. Staples Department of Chemical Engineering Master of Science Chemotherapy is one of the most successful cancer treatments used today. Unfortunately, the amount of chemotherapy a patient can receive is limited by the associated negative side effects, such as cardiotoxicity, immune system suppression, and nephrotoxicity. Encapsulation of these drugs, Doxorubicin (DOX) in particular, in stabilized Pluronic micelles (Plurogel) shows success in limiting these harmful side effects. In previous studies, low-frequency ultrasound (US) has been shown, in vitro, to locally release DOX from these micelles. In this study, a novel drug delivery system involving the encapsulation of DOX in Plurogel and the release of the drug at the tumor site using ultrasound was studied in vivo using rats. These studies determined the effect of ultrasonically released drugs on tumor growth rate and drug delivery to the tumor tissue. Concurrently, different frequencies (20 kHz, 500 kHz) were tested for the same effects. Treatments consisted of micelle-encapsulated doxorubicin injected intravenously followed by ultrasound application to one of the two bilateral tumors. Also, in different experiments, pharmacokinetic studies of the drug in the heart, liver, leg muscle, and tumors were performed up to a period of one week after treatment. Results showed that tumors treated with ultrasound displayed, on average, slower growth rates than non-insonated tumors (P = 0.0047). Also, insonated tumors displayed a weak increased concentration of DOX than non-insonated tumors within the first eight hours after treatment (P = 0.064). However, comparison between tumors which received 20 kHz and 500 kHz ultrasound treatment showed no statistical difference (P = 0.9275) in tumor growth rate or DOX concentration. It is noteworthy that the insonated tumor has slower growth even though the amount of DOX was not that much greater in the noninsonated tumor. This suggests that US also affects the uptake and/or processing of the DOX by the tumor cells, and that the therapeutic effect may not be attributed solely to a higher concentration of drug released by insonation. Pharmacokinetic studies showed significant drug accumulation in the heart but no accumulation in the liver, skeletal leg muscle, or tumors over the course of four weeks of consecutive weekly injections of DOX-encapsulated Plurogel. After 24 hours, DOX concentration remains the greatest in the tumors, regardless of whether they received

/pdf/pharmacokinetics-of-ultrasonically-released-micelle-2xuskxjien.pdf

Pharmacokinetics of Ultrasonically-Released, Micelle-Encapsulated Doxorubicin in the Rat Model and its Effect on Tumor Growth

/pdf/quantification-of-doxorubicin-concentration-in-rat-tissues-4dsm8vs6c4.pdf

Bryant J. Staples

Papers

Ultrasonic Drug Delivery – A General Review

Distribution of Doxorubicin in Rats Undergoing Ultrasonic Drug Delivery

Role of frequency and mechanical index in ultrasonic-enhanced chemotherapy in rats

Pharmacokinetics of Ultrasonically-Released, Micelle-Encapsulated Doxorubicin in the Rat Model and its Effect on Tumor Growth

Quantification of Doxorubicin Concentration in Rat Tissues using Polymeric Micelles in Ultrasonic-Drug Delivery