Design of an ultrasonic physiotherapy system with pulse wave feedback control.

BACKGROUND: Due to different physical and biological mechanisms behind ultrasound hyperthermia and phonophoresis, the requirement for ultrasound power, frequency and control modes varies. OBJECTIVE: This paper introduces an adaptive ultrasonic physiotherapy system based on real-time surveillance over physiological characteristics of the patients, which in turn assists the individual treatment and dose limitation in auxiliary rehabilitation. METHODS: The method essentially takes advantage of distinctive characteristics of two different phases (systole and diastole) of the human cardiac cycle as a medium for modulation. The abundance of blood flow during systole enables energy exchange for hyperthermia while blood flow insufficiency caused by diastole assists in drug penetration. Said method could improve the adjuvant therapy as it provides partial drug penetration and therapeutic dosage control. RESULTS: By adjusting time window and intensity of multi-frequency ultrasound, it is possible to reduce the irradiation dosage to around 22% of that during continuous irradiation at 1 MHz. The method shows high potential in clinical practice. CONCLUSION: Frequency-tuning ultrasound therapy would be more efficient regarding drug penetration and improve the therapeutic efficacy of hyperthermia.

Pulsed High-Intensity Focused Ultrasound Enhances Delivery of Doxorubicin in a Preclinical Model of Pancreatic Cancer.

Pancreatic cancer is characterized by extensive stromal desmoplasia, which decreases blood perfusion and impedes chemotherapy delivery. Breaking the stromal barrier could both increase perfusion and permeabilize the tumor, enhancing chemotherapy penetration. Mechanical disruption of the stroma can be achieved using ultrasound-induced bubble activity-cavitation. Cavitation is also known to result in microstreaming and could have the added benefit of actively enhancing diffusion into the tumors. Here, we report the ability to enhance chemotherapeutic drug doxorubicin penetration using ultrasound-induced cavitation in a genetically engineered mouse model (KPC mouse) of pancreatic ductal adenocarcinoma. To induce localized inertial cavitation in pancreatic tumors, pulsed high-intensity focused ultrasound (pHIFU) was used either during or before doxorubicin administration to elucidate the mechanisms of enhanced drug delivery (active vs. passive drug diffusion). For both types, the pHIFU exposures that were associated with high cavitation activity resulted in disruption of the highly fibrotic stromal matrix and enhanced the normalized doxorubicin concentration by up to 4.5-fold compared with controls. Furthermore, normalized doxorubicin concentration was associated with the cavitation metrics (P < 0.01), indicating that high and sustained cavitation results in increased chemotherapy penetration. No significant difference between the outcomes of the two types, that is, doxorubicin infusion during or after pHIFU treatment, was observed, suggesting that passive diffusion into previously permeabilized tissue is the major mechanism for the increase in drug concentration. Together, the data indicate that pHIFU treatment of pancreatic tumors when resulting in high and sustained cavitation can efficiently enhance chemotherapy delivery to pancreatic tumors. .

Recent advances in physical delivery enhancement of topical drugs.

The skin has evolved to resist the penetration of foreign substances and particles. Effective topical drug delivery into and/or through the skin is hindered by these epidermal barriers. A range of physical enhancement methods has been developed to selectively overcome this barrier. This review discusses recent advances in physical drug delivery by broadly separating the techniques into two main areas; indirect and direct approaches. Indirect approaches consist of electrical, vibrational or laser instrumentation that creates pores in the skin followed by application of the drug. Direct approaches consist of mechanical disruption of the epidermis using techniques such as microdermabrasion, biolistic injectors and microneedles. Although, in general, physical techniques are yet to be established in a clinical setting, the potential gains of enhancing delivery of compounds through the skin is of great significance and will no doubt continue to receive much attention.

The effect of sonophoresis on topical anesthesia: a pilot project.

The dental anesthesia sonophoresis device (DASD) is a novel device that is intended to reduce the discomfort associated with intraoral mucosa needle puncture. The DASD produces ultrasonic energy that provides a sonophoretic effect on the oral mucosa, generating microchannels through the lipids between the keratinized cells that make up the stratum corneum. Once the topical anesthetic has permeated the stratum corneum, it quickly diffuses through the soft tissue, desensitizing the nerve endings and reducing the perception of pain caused by needle penetration. The aim of this study is to evaluate whether topical anesthesia applied using the DASD will reduce the discomfort of the needle puncture when compared to the control device. A split-mouth model, using 50 healthy subjects with puncture site at the maxillary canine vestibule, was used for this study. Subjects received a needle puncture on both sides of the mouth. Prior to the needle puncture, there was randomized application of 5% lidocaine with the DASD and a control device. Subjects rated their discomfort after needle punctures utilizing the visual analog scale pain scoring system. There was no statistically significant difference in the pain perception using the DASD versus the control device.

The effect of SonoPrep® on EMLA® cream application for pain relief prior to intravenous cannulation.

The aim the study was to determine the effect of SonoPrep® on the delivery and analgesic effects of EMLA® cream prior to intravenous (iv) cannulation in a tertiary pediatric emergency department. Children aged between 5 and 10 years were enrolled. Patients were randomized to receive either sonophoresis with SonoPrep® or sham sonophoresis followed by application of EMLA® cream for 5 min prior to iv cannulation. The primary outcome measurement was the child's rating of pain immediately after iv placement, using a 10-cm visual analog scale (VAS). Parents or guardians and blinded researchers were additionally asked to rate their perception of the child's pain using the 10-cm VAS and the Wong-Baker Face scale. A total of 42 patients completed the study (21 in the study group, 21 in the control group). The baseline characteristics between the groups were similar. The VAS pain score was significantly lower in children treated with sonophoresis compared with the sham sonophoresis (median (percentiles 25th-75th), 20.0 (10.0-22.5) vs. 60.0 (31.0-87.5); p < 0.001). The parent's perception of the child's pain was significantly lower in the study group vs. the control group by the VAS (median (percentiles 25th-75th), 10.0 (10.0-20.0) vs. 50.0 (15.0-80.0); p < 0.001) and Wong-Baker Face scale (median (percentiles 25th-75th), 2.0 (2.0-2.0) vs. 4.0 (2.5-4.5); p < 0.001). The researcher's evaluation of the child's discomfort was also significantly lower in the study group (2.0 (1.0-3.0) vs. 4.0 (2.5-4.5); p < 0.001). The application of sonophoresis using SonoPrep® followed by the 5-min application of EMLA® cream showed significant benefit in young children in terms of pain reduction and patient satisfaction.

Efficiency of low-frequency ultrasound sonophoresis in skin penetration of histamine: a randomized study in humans.

Low-frequency ultrasound (US) applied to skin (sonophoresis) has been investigated to enhance the transdermal transport of various drugs. Histamine is usually used in allergy investigations. We aimed to investigate, in a randomized study, the transdermal penetration of histamine with sonophoresis. Ten subjects were included. Their right forearm was divided into three zones, which were randomly assigned a treatment: no US, US(1) (I(1)=2.72 W/cm(2)), US(2) (I(2)=3.50 W/cm(2)). The primary outcome was area of induced papule, which revealed histamine penetration. Secondary outcomes were echographic measurement of papule (skin thickness) and pruritus. Measurements were taken immediately after US application and after 30 min, 2 h and 24 h. Arm zones without US application showed no papules induced by histamine; 9/10 subjects receiving US showed papules. Their mean size increased with increased intensity of US but not significantly. The skin thickness increased with US. Pruritus occurred in 7/10 cases after US and histamine. The adverse events were skin erythema, pain and tinnitus. Though this study included a few number of patients, it confirms that sonophoresis enhances skin penetration of histamine. This technology could be used at therapeutic levels: histamine could be used with sonophoresis as a positive control in allergy testing instead of prick tests, which involve skin disruption with a lancet.

Modulation control over ultrasound-mediated gene delivery: evaluating the importance of standing waves.

Low modulation frequencies from 0.5 to 100Hz were shown to alter the characteristics of the ultrasound field producing solution agitation (<5Hz; region of "ultrasound streaming" prevalence) or stagnancy (>5Hz; region of standing waves establishment) (Buldakov et al., Ultrason. Sonochem., 2009). In this study, the same conditions were used to depict the changes in exogenous DNA delivery in these regions. The luciferase expression data revealed that lower modulations were more capable of enhancing delivery at the expense of viability. On the contrary, the viability was conserved at higher modulations whereas delivery was found to be null. Cavitational activity and acoustic streaming were the effecters beyond the observed pattern and delivery enhancement was shown to be mediated mainly through sonopermeation. To promote transfection, the addition of calcium ions or an echo contrast agent (Levovist((R))) was proposed. Depending on the mechanism involved in each approach, differential enhancement was observed in both regions and at the interim zone (5Hz). In both cases, enhancement in standing waves field was significant reaching 16.0 and 3.3 folds increase, respectively. Therefore, it is concluded that although the establishment of standing waves is not the only prerequisite for high transfection rates, yet, it is a key element in optimization when other factors such as proximity and cavitation are considered.

Acoustic cavitation as an enhancing mechanism of low-frequency sonophoresis for transdermal drug delivery.

We investigated the role of acoustic cavitation on sonophoretic skin permeation of calcein, a model permeant, across excised hairless rat skin. Three different frequencies (41, 158, 445 kHz) and various intensities (60 to 300 mW/cm(2)) of ultrasound were applied. Cavitation generation in degassed and undegassed (normal) water was monitored using a commercially available cavitation meter, then compared with skin permeability from calcein solution consistent of them. In addition, the penetration of a fluorescent dye, rhodamine B, into gelatin gel as a skin alternative was observed to estimate the role of cavitation collapse in the solution at or near the skin surface. Cavitation generation in the undegassed water was dependent on the ultrasound frequency, and the rank order of the cavitation was 41 kHz>158 kHz>445 kHz. At 41 kHz, cavitation generation in degassed water was clearly lower than that in undegassed water. Calcein permeability during ultrasound application correlated well with the cavitation generation in the medium, suggesting the important role of the indirect actions of cavitation collapse which occurred in the applied solution rather than the direct action in the skin. When ultrasound (41 or 158 kHz) was applied to the gelatin gels covered with rhodamine B solution, alteration in the surface configuration, like spots, and the coincident penetration of the dye were observed only at 41 kHz, while no alteration in the surface configuration was evident at 158 kHz. These results suggest that cavitation collapses in the vicinity of the skin surface might be more important for solute penetration in addition to skin permeabilization.

Design and experimental evaluations of a low-frequency hemispherical ultrasound phased-array system for transcranial blood-brain barrier disruption.

The purpose of this paper is to demonstrate a prototype design of a low-frequency multiple-channel hemispherical focused-ultrasound phased-array system for transcranial disruption of the blood-brain barrier (BBB). A 32-channel ultrasound driving system tunable in the frequency range from 200 to 400 kHz was designed for producing a suitable ultrasound output for BBB disruption. The driving system includes a microcontroller/field-programmable gate-array-based control kernel with multiple-channel driving circuits implemented by a high-voltage switching/LC-resonance/impedance-matching circuit module. Three hemispherical phased arrays comprising 22, 31, and 80 elements were fabricated and tested. The pressure distributions at the geometric center and at off-center positions were tested experimentally. The focal performance of the different hemispherical arrays was also evaluated theoretically. The results showed that the developed phased-array system can successfully drive the hemispherical array with multiple-channel ultrasound signals with independent phase control at 8-bit resolution. Good focusing abilities were evident both at the geometric center and at specific off-center target positions. Preliminary animal experiments show that the BBB in rat can be locally disrupted successfully. The system will serve as a reference platform for developing a focused-ultrasound system for clinical use in brain drug delivery applications.

Rectangular cymbal arrays for improved ultrasonic transdermal insulin delivery.

Circular cymbal ultrasound arrays have been shown to be effective in delivering therapeutic levels of insulin in rats, rabbits, and pigs. To improve delivery efficiency, a rectangular cymbal design was desired in order to achieve a broader spatial intensity field without increasing the size of the device or the spatial-peak temporal-peak intensity (I(SPTP)). With a similar intensity (50 mWcm(2)), the goal was to determine if the 3x1 rectangular cymbal array could perform significantly better than the 3x3 circular array for glucose reduction in hyperglycemic rabbits. Rabbit experiments were performed using three groups: nonsonicated control (n=3), ultrasound exposure using a circular cymbal array (n=3), and ultrasound exposure using a rectangular cymbal array (n=3). Rabbits were anesthetized and a water tight reservoir that held the insulin was fastened on the rabbit's thigh. At the beginning of the experiment and every 15 min for 90 min, the blood glucose level was determined. For comparison between individual rabbits, the absolute level is normalized by subtracting out the baseline in order to arrive at the change in glucose level. For the control group, the normalized glucose level increased (more hyperglycemic) to +80.0+/-28.8 mgdl (mean+/-SEM). Using the circular array, the glucose level decreased to -146.7+/-17.8 mgdl at 90 min. However, using the rectangular cymbal array, the glucose decreased faster and to a level of -200.8+/-5.9 mgdl after 90 min. These results indicated the feasibility of the rectangular cymbal array as an improved device for drug delivery.

Ultrasound mediated transdermal insulin delivery in pigs using a lightweight transducer.

PURPOSE: In previous studies, ultrasound mediated transdermal drug delivery has shown a promising potential as a method for noninvasive drug administration. For prospective future human application, this study was designed to determine the feasibility of lightweight cymbal transducer array as a practical device for noninvasive transdermal insulin delivery in large pigs. MATERIALS AND METHODS: Six Yorkshire pigs (100-140 lbs) were divided into two groups. As the control (n = 3), the first group did not receive any ultrasound exposure with the insulin. The second group (n = 3) was treated with ultrasound and insulin at 20 kHz with an I(sptp) = 100 mW/cm(2) at a 20% duty cycle for 60 min. With the pigs in lateral recumbency after anesthesia, the ultrasound transducer with insulin was placed on the axillary area of the pig. At the beginning and every 15 min up to 90 min, the blood glucose level was determined using a glucose monitoring system. To compare the results of individual animals, the change of blood glucose level was normalized to each animal's initial glucose value at the start of the experiment. RESULTS: Although each animal had a different initial glucose level, the mean and standard error for the six animals was 146 +/- 13 mg/dl. For the control group, the blood glucose level increased to 31 +/- 21 mg/dl compared to the initial baseline over the 90 min experiment. However for the ultrasound with insulin treated group, the glucose level decreased to -72 +/- 5 mg/dl at 60 min (p < 0.05) and continued to decrease to -91 +/- 23 mg/dl in 90 min (p < 0.05). CONCLUSION: The results indicate the feasibility of ultrasound mediated transdermal insulin delivery using the cymbal transducer array in animal with a similar size and weight to a human. Based on these result, the cymbal array has potential as a practical ultrasound system for noninvasive transdermal insulin delivery for diabetes management.

Therapeutic applications of ultrasound.

Therapeutic applications of ultrasound predate its use in imaging. A range of biological effects can be induced by ultrasound, depending on the exposure levels used. At low levels, beneficial, reversible cellular effects may be produced, whereas at high intensities instantaneous cell death is sought. Therapy ultrasound can therefore be broadly divided into "low power" and "high power" applications. The "low power" group includes physiotherapy, fracture repair, sonophoresis, sonoporation and gene therapy, whereas the most common use of "high power" ultrasound in medicine is probably now high intensity focused ultrasound. Therapeutic effect through the intensity spectrum is obtained by both thermal and non-thermal interaction mechanisms. At low intensities, acoustic streaming is likely to be significant, but at higher levels, heating and acoustic cavitation will predominate. While useful therapeutic effects are now being demonstrated clinically, the mechanisms by which they occur are often not well understood.

Dermal and transdermal drug delivery systems: current and future prospects.

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 adequate lipophilicity and also a molecular weight <500 Da. These requirements have limited the number of commercially available products based on transdermal or dermal delivery. Various strategies have emerged over recent years to optimize delivery and these can be categorized into passive and active methods. The passive approach entails the optimization of formulation or drug carrying vehicle to increase skin permeability. Passive methods, however do not greatly improve the permeation of drugs with molecular weights >500 Da. In contrast active methods that normally involve physical or mechanical methods of enhancing delivery have been shown to be generally superior. Improved delivery has been shown for drugs of differing lipophilicity and molecular weight including proteins, peptides, and oligonucletides using electrical methods (iontophoresis, electroporation), mechanical (abrasion, ablation, perforation), and other energy-related techniques such as ultrasound and needless injection. However, 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. This article provides a detailed review of the next generation of active delivery technologies.

Low-frequency sonophoresis: a review.

Application of ultrasound enhances skin permeability to a variety of molecules (sonophoresis). The enhancement induced by ultrasound is particularly significant at low-frequencies (f<100 kHz, low-frequency sonophoresis). This review summarizes mechanisms and applications of low-frequency sonophoresis. In vitro, in vivo, as well as clinical studies demonstrating the effect of low-frequency ultrasound on transdermal drug delivery and glucose extraction are summarized. Mechanistic insights gained through a number of investigations are also reviewed. Finally, reports on the synergistic effect of low-frequency ultrasound with other enhancers including chemicals and iontophoresis are summarized.

Ultrasound-mediated transdermal in vivo transport of insulin with low-profile cymbal arrays.

The purpose of this study was to demonstrate the feasibility of ultrasound (US)-mediated transdermal delivery of insulin in vivo using rats with a novel, low profile two-by-two US array based on the "cymbal" (due to its unique shape) transducer. As a practical device, the cymbal array (f = 20 kHz) was 37 x 37 x 7 mm in size, and weighed less than 22 g. A total of 20 Sprague-Dawley rats (350 to 450 g) were divided into four groups, two controls and two US exposure, with five rats in each group. The rats were anesthetized and shaved; a water-tight standoff reservoir, which held the insulin or saline, was sealed against the rat's abdomen and the US array. At the beginning of the experiment and every 30 min for 90 min, 0.3 mL of blood was collected from the jugular vein to determine the blood glucose level (mg/dL). For comparison between the rats, the change in the glucose level for each rat was normalized to a baseline (i.e., 0 mg/dL). The first control group used insulin in the reservoir with no US and the second control group had saline in the reservoir with US operating at I(SPTP) = 100 mW/cm(2) for 60 min. For the experiments, the third group employed insulin with US exposure for 60 min (I(SPTP) = 100 mW/cm(2)), whereas the last group used insulin with US operating with a 20-min exposure (I(SPTP) = 100 mW/cm(2)) to examine the effects of time on delivery. For the 60-min US exposure group, the glucose level was found to decrease from the baseline to -267.5 +/- 61.9 mg/dL in 1 h. Moreover, to study the effects of US exposure time on insulin delivery, the 20-min group had essentially the same result as the 60-min exposure at a similar intensity, which indicates that the expose time does not need to be as long for delivery.

Phonophoresis: efficiency, mechanisms and skin tolerance.

Phonophoresis or sonophoresis is the use of ultrasound to increase percutaneous absorption of a drug. The technique has been widely used in sports medicine since the sixties. Controlled studies in humans in vivo have demonstrated absence or mild effects of the technique with the parameters currently used (frequency 1-3 MHz, intensity 1-2 W/cm(2), duration 5-10 mins, continuous or pulse mode). However, it was demonstrated in 1995 that administration of macromolecules with conserved biological activity was feasible in animals in vivo using low frequency ultrasound. This led to new research into this method of transdermal administration. The aim of this review is to present the main findings published with low frequency and high frequency ultrasound over the last ten years, and to discuss the respective roles of thermal, cavitational and non-cavitational effects on the reduction of the skin barrier. Particular attention is paid to the biological effects on living skin which might be of importance for tolerance and practical use in humans.

Dependence of low-frequency sonophoresis on ultrasound parameters; distance of the horn and intensity.

Sonophoresis at a frequency of 20 kHz has been shown to enhance transdermal drug delivery, a phenomenon referred to as low-frequency sonophoresis. This study provides an investigation of the dependence of low-frequency sonophoresis on various ultrasound parameters, including the distance of the horn from the skin, intensity, and frequency. We performed in vitro experiments with full thickness pig skin to measure enhancements of skin conductivity and drug permeability. Ultrasound was applied to pretreat the skin using a sonicator operating at a frequency of either 20 or 40 kHz. We also measured pitting of aluminum foil to measure cavitation, which is the principal mechanism of low-frequency sonophoresis. The skin conductivity enhancement was found to be inversely proportional to the distance of the horn from the skin. As the intensity increased, skin conductivity enhancement also increased up to a certain threshold, and then dropped off. The intensities (I(max)) at which maximum enhancement occur are about 14 W/cm2 for 20 kHz and 17 W/cm2 for 40 kHz. These findings may be useful in optimizing low-frequency sonophoresis. Overall, the dependence of transport on ultrasound parameters is similar to that of aluminum foil pitting. These results support the role of cavitation in low-frequency sonophoresis.

Novel mechanisms and devices to enable successful transdermal drug delivery.

Optimisation of drug delivery through human skin is important in modern therapy. This review considers drug-vehicle interactions (drug or prodrug selection, chemical potential control, ion pairs, coacervates and eutectic systems) and the role of vesicles and particles (liposomes, transfersomes, ethosomes, niosomes). We can modify the stratum corneum by hydration and chemical enhancers, or bypass or remove this tissue via microneedles, ablation and follicular delivery. Electrically assisted methods (ultrasound, iontophoresis, electroporation, magnetophoresis, photomechanical waves) show considerable promise. Of particular interest is the synergy between chemical enhancers, ultrasound, iontophoresis and electroporation.