Journal Article•
Perspectives on transdermal ultrasound mediated drug delivery.
TL;DR: A broad review of the transdermal ultrasound drug delivery literature has shown that this technology offers promising potential for noninvasive drug administration, and the proposed mechanism of ultrasound has been suggested to be the result of cavitation, which is discussed along with the bioeffects from therapeutic ultrasound.
Abstract: The use of needles for multiple injection of drugs, such as insulin for diabetes, can be painful. As a result, prescribed drug noncompliance can result in severe medical complications. Several noninvasive methods exist for transdermal drug delivery. These include chemical mediation using liposomes and chemical enhancers or physical mechanisms such as microneedles, iontophoresis, electroporation, and ultrasound. Ultrasound enhanced transdermal drug delivery offers advantages over traditional drug delivery methods which are often invasive and painful. A broad review of the transdermal ultrasound drug delivery literature has shown that this technology offers promising potential for noninvasive drug administration. From a clinical perspective, few drugs, proteins or peptides have been successfully administered transdermally because of the low skin permeability to these relatively large molecules, although much work is underway to resolve this problem. The proposed mechanism of ultrasound has been suggested to be the result of cavitation, which is discussed along with the bioeffects from therapeutic ultrasound. For low frequencies, potential transducers which can be used for drug delivery are discussed, along with cautions regarding ultrasound safety versus efficacy.
Citations
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TL;DR: This review highlights gene therapy as a new promising technique used to treat many incurable diseases and the different strategies used to transfer DNA, taking into account that introducing DNA into the cell nucleus without degradation is essential for the success of this therapeutic technique.
388 citations
TL;DR: This work reviews systems employing synergistic mixtures of chemicals that offer superior skin permeation enhancement and methods for design and discovery of such synergistic systems are discussed.
323 citations
TL;DR: A broad overview of bio-effects and safety of LF ultrasound as an aid to minimize and control the risk of these effects is presented and an improved formulation for the MI is proposed for frequencies below 500 kHz.
Abstract: Low-frequency (LF) ultrasound (20e100 kHz) has a diverse set of industrial and medical applications. In fact, high power industrial applications of ultrasound mainly occupy this frequency range. This range is also used for various therapeutic medical applications including sonophoresis (ultrasonic transdermal drug delivery), dentistry, eye surgery, body contouring, the breaking of kidney stones and eliminating blood clots. While emerging LF applications such as ultrasonic drug delivery continue to be developed and undergo translation for human use, significant gaps exist in the coverage of safety standards for this frequency range. Accordingly, the need to understand the biological effects of LF ultrasound is becoming more important. This paper presents a broad overview of bio-effects and safety of LF ultrasound as an aid to minimize and control the risk of these effects. Its particular focus is at low intensities where bio-effects are initially observed. To generate a clear perspective of hazards in LF exposure, the mechanisms of bio-effects and the main differences in action at low and high frequencies are investigated and a survey of harmful effects of LF ultrasound at low intensities is presented. Mechanical and thermal indices are widely used in high frequency diagnostic applications as a means of indicating safety of ultrasonic exposure. The direct application of these indices at low frequencies needs careful investigation. In this work, using numerical simulations based on the mathematical and physical rationale behind the indices at high frequencies, it is observed that while thermal index (TI) can be used directly in the LF range, mechanical index (MI) seems to become less reliable at lower frequencies. Accordingly, an improved formulation for the MI is proposed for frequencies below 500 kHz.
171 citations
Cites background from "Perspectives on transdermal ultraso..."
...As observed in this table, the literature on the safety of this type of exposure is sparse and is mainly concerned with sonophoresis applications (Mitragotri, 1996, 2005; Mitragotri and Kost, 2004; Lavon and Kost, 2004; Machet and Boucaud, 2002; Ogura et al., 2008; Pahade et al., 2010; Smith, 2007)....
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TL;DR: Novel theoretical and experimental approaches have provided insights into the mechanisms of low-frequency sonophoresis and current understanding of these mechanisms is presented.
159 citations
References
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TL;DR: Ultrasound, which is routinely used for diagnostic imaging applications, is now being adopted in various drug delivery and other therapeutic applications, and the principles and current status are reviewed.
Abstract: Ultrasound, which is routinely used for diagnostic imaging applications, is now being adopted in various drug delivery and other therapeutic applications. Ultrasound has been shown to facilitate the delivery of drugs across the skin, promote gene therapy to targeted tissues, deliver chemotherapeutic drugs into tumours and deliver thrombolytic drugs into blood clots. In addition, ultrasound has also been shown to facilitate the healing of wounds and bone fractures. This article reviews the principles and current status of ultrasound-based treatments.
813 citations
"Perspectives on transdermal ultraso..." refers background in this paper
...Many recent reviews have shown that ultrasound mediated transdermal drug delivery offers promising potential for noninvasive drug administration (Tachibana and Tachibana 2001; Pitt et al 2004; Mitragotri 2005)....
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...Many recent reviews have shown that ultrasound medi- ated transdermal drug delivery offers promising potential for noninvasive drug administration (Tachibana and Tachibana 2001; Pitt et al 2004; Mitragotri 2005)....
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TL;DR: Low-frequency ultrasound was shown to increase the permeability of human skin to many drugs, including high molecular weight proteins, by several orders of magnitude, thus making transdermal administration of these molecules potentially feasible.
Abstract: Transdermal drug delivery offers a potential method of drug administration. However, its application has been limited to a few low molecular weight compounds because of the extremely low permeability of human skin. Low-frequency ultrasound was shown to increase the permeability of human skin to many drugs, including high molecular weight proteins, by several orders of magnitude, thus making transdermal administration of these molecules potentially feasible. It was possible to deliver and control therapeutic doses of proteins such as insulin, interferon gamma, and erythropoeitin across human skin. Low-frequency ultrasound is thus a potential noninvasive substitute for traditional methods of drug delivery, such as injections.
803 citations
"Perspectives on transdermal ultraso..." refers background in this paper
...The working principle of sonophoresis, although not completely understood, has been suggested to be the result of cavitation (Mitragotri et al 1995b, 1997) although thermal effects can not be entirely discounted....
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...Past research has demonstrated the possibility of deliv- ering and controlling therapeutic doses of proteins such as interferon gamma and erythropoeitin across human skin using ultrasound (Mitragotri et al 1995a)....
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...Although ultrasound is known to increase transdermal pro- tein delivery (Tachibana 1992; Mitragotri et al 1995a) the mechanisms of this enhanced transport have not been fully characterized (Pitt et al 2004)....
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...One hypothesis indicates that once the drug has traversed the stratum corneum, the next layer is easier to cross and subsequently the drug can reach the capil- lary vessels to be absorbed (Mitragotri et al 1995b)....
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TL;DR: An index is developed which can gauge the likelihood of substantial microbubble growth in the presence of short-pulse, low-duty cycle diagnostic ultrasound.
Abstract: Although no deleterious effects form diagnostic ultrasound have been reported in epidemiologic studies and surveys of widespread clinical usage (Ziskin and Petitti 1988), the conditions for the onset of transient cavitation must be investigated in the total evaluation of potential risks associated with diagnostic ultrasound applications. An extension of the results from the approximate theory developed by Holland and Apfel (1989) is applied in this paper to a population of nuclei to predict the onset of cavitation in host fluids with physical properties similar to those of biological fluids. From this analysis and from results of recent in vitro cavitation experiments, an index is developed which can gauge the likelihood of substantial microbubble growth in the presence of short-pulse, low-duty cycle diagnostic ultrasound.
644 citations
TL;DR: This selective review of the biological effects of ultrasound presents a synopsis of the current understanding of how cells insonated in vitro are affected by inertial cavitation from the standpoint of physical and chemical mechanisms.
Abstract: This selective review of the biological effects of ultrasound presents a synopsis of our current understanding of how cells insonated in vitro are affected by inertial cavitation from the standpoint of physical and chemical mechanisms. The focus of this review is on the physical and chemical mechanisms of action of inertial cavitation which appear to be effective in causing biological effects. There are several fundamental conditions which must be satisfied before cavitation-related bioeffects may arise. First, bubbles must be created and then brought into proximity to cells. Exposure methods are critical in this regard, and simple procedures such as rotation of a vessel containing the cells during exposure can drastically alter the results. Second, once association is achieved between bubbles and cells, the former must interact with the latter to produce a bioeffect. It is not certain that the inertial event is the prime mechanism by which cells are lysed; there is evidence that the turbulence associated with bubble translation may cause lysis. Additionally, there appear to be chemical and other physical mechanisms by which inertial cavitation may affect cells; these include the generation of biologically effective sonochemicals and the apparent emission of ultraviolet (UV) and soft X-rays. The evidence for inertial cavitation occurring within cells is critically reviewed.
577 citations
"Perspectives on transdermal ultraso..." refers background in this paper
...Beyond the threshold, cavitation has been shown to disrupt cells and damage tissue (Dalecki et al 1996; Miller et al 1996)....
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TL;DR: For these novel delivery methods to succeed and compete with those already on the market, the prime issues that require consideration include device design and safety, efficacy, ease of handling, and cost-effectiveness.
Abstract: The protective function of human skin imposes physicochemical limitations to the type of permeant that can traverse the barrier. For a drug to be delivered passively via the skin it needs to have a...
557 citations
"Perspectives on transdermal ultraso..." refers background in this paper
...Additionally for transdermal work, the reader is also directed to several well written articles for further reading and additional viewpoints on this topic (Mitragotri and Kost 2004; Pitt et al 2004; Brown et al 2006)....
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...Passive drug delivery across the stratum corneum can be transported with molecules that have a weight less than 500 Da (Brown et al 2006)....
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