Feasibility of in vivo transesophageal cardiac ablation using a phased ultrasound array.

Over 2.2 million Americans suffer from atrial fibrillation making it one of the most common arrhythmias. Cardiac ablation has shown a high rate of success in treating paroxysmal atrial fibrillation. Prevailing modalities for this treatment are catheter based radio-frequency ablation or surgery. However, there is measurable morbidity and significant costs and time associated with these invasive procedures. Due to these issues, developing a method that is less invasive to treat atrial fibrillation is needed. In the development of such a device, a transesophageal ultrasound applicator for cardiac ablation was designed, constructed and evaluated. A goal of this research was to create lesions in myocardial tissue using a phased array. Based on multiple factors from array simulations, transesophageal imaging devices and throat anatomy, a phased ultrasound transducer that can be inserted into the esophagus was designed and tested. In this research, a two-dimensional sparse phased array with the aperture size of 20.7 mm x 10.2 mm with flat tapered elements as a transesophageal ultrasound applicator was fabricated and evaluated with in vivo experiments. Five pigs were anesthetized; the array was passed through the esophagus and positioned over the heart. The array was operated for 8-15 min at 1.6 MHz with the acoustic intensity of 150-300 W/cm(2) resulting in both single and multiple lesions on atrial and ventricular myocardium. The average size of lesions was 5.1 +/- 2.1 mm in diameter and 7.8 +/- 2.5 mm in length. Based on the experimental results, the array delivered sufficient power to the focal point to produce ablation while not grossly damaging nearby tissue outside the target area. These results demonstrate a potential application of the ultrasound applicator to transesophageal cardiac surgery in atrial fibrillation treatment.

Noninvasive ultrasonic glucose sensing with large pigs (approximately 200 pounds) using a lightweight cymbal transducer array and biosensors.

BACKGROUND: To prevent complications in diabetes, the proper management of blood glucose levels is essential. Since conventional glucose meters require pricking fingers or other areas of the skin, a noninvasive method for monitoring blood glucose levels is desired. Using a lightweight cymbal transducer array, this study was conducted to noninvasively determine the glucose levels of pigs having a similar size to humans. METHOD: In vivo experiments using eight pigs (approximately 200 pounds) were performed in five groups. A cymbal array with four biosensors was attached to the axillary area of the pig. The array was operated at 20 kHz at special peak-temporal peak intensity (I(sptp)) equal to 50 or 100 mW/cm(2) for 5, 10, or 20 minutes. After the ultrasound exposure, glucose concentrations of the interstitial fluid were determined using biosensors. For comparison, glucose levels of blood samples collected from the ear vein were measured by a commercial glucose meter. RESULT: In comparison, glucose levels determined by a cymbal array and biosensor system were close to those measured by a glucose meter. After a 20-minute ultrasound exposure at I(sptp) = 100 mW/cm(2), the average glucose level determined by the ultrasound system was 175 +/- 7 mg/dl, which is close to 166 +/- 5 mg/dl measured by the glucose meter. CONCLUSION: Results indicate the feasibility of using a cymbal array for noninvasive glucose sensing on pigs having a similar size to humans. Further studies on the ultrasound conditions, such as frequency, intensity, and exposure time, will be continued for effective glucose sensing.

End-element anomalies in medical ultrasonic piezo-composite arrays.

Piezoelectric composites are commonly used in medical diagnostic ultrasonic imaging arrays. The performance of the array elements at either end of the array can differ from that of array elements away from the ends. There is some general understanding about the origin of these effects (such as different acoustic impedance), and some standard compensatory designs exist (such as adding unused array elements further on the end than the last used array element). This work seeks to elucidate the origins of these end-element anomalies and to propose corresponding design changes. A commercially produced array with notable end-element anomalies is examined as a case study. Results from experiments and finite element analysis indicate that, in the presence of a stiffness discontinuity within the composite (such as poled elements adjacent to unpoled ones), a secondary wave that propagates laterally through the composite may be generated during the receive transduction. This wave appears to cause the anomalous behavior observed in the signals and metrics of the end elements. Changing the electrical loading of an element and poling the unused, previously unpoled elements are explored as anomaly-mitigating design alterations. The latter of these 2 initially appears to be the more effective solution.

Dose comparison of ultrasonic transdermal insulin delivery to subcutaneous insulin injection.

Prior studies have demonstrated the effectiveness of noninvasive transdermal insulin delivery using a cymbal transducer array. In this study the physiologic response to ultrasound mediated transdermal insulin delivery is compared to that of subcutaneously administered insulin. Anesthetized rats (350-550 g) were divided into four groups of four animals; one group representing ultrasound mediated insulin delivery and three representing subcutaneously administered insulin (0.15, 0.20, and 0.25 U/kg). The cymbal array was operated for 60 minutes at 20 kHz with 100 mW/cm2 spatial-peak temporal-peak intensity and a 20% duty cycle. The blood glucose level was determined at the beginning of the experiment and, following insulin administration, every 15 minutes for 90 minutes for both the ultrasound and injection groups. The change in blood glucose from baseline was compared between groups. When administered by subcutaneous injection at insulin doses of 0.15 and 0.20 U/kg, there was little change in the blood glucose levels over the 90 minute experiment. Following subcutaneous administration of insulin at a dose of 0.25 U/kg, blood glucose decreased by 190 +/- 96 mg/dl (mean +/- SD) at 90 minutes. The change in blood glucose following ultrasound mediated insulin delivery was -262 +/- 40 mg/dl at 90 minutes. As expected, the magnitude of change in blood glucose between the three injection groups was dependant on the dose of insulin administered. The change in blood glucose in the ultrasound group was greater than that observed in the injection groups suggesting that a higher effective dose of insulin was delivered.

Targeting V600EB-Raf and Akt3 using nanoliposomal-small interfering RNA inhibits cutaneous melanocytic lesion development.

Most events promoting early melanoma development are yet to be identified, but deregulation of the B-Raf and Akt3 signaling cascades is an important regulator of this process. Approximately 90% of normal moles and approximately 60% of early invasive cutaneous melanomas contain a T1799A B-Raf mutation ((V600E)B-Raf), leading to 10 times higher enzyme activity and constitutive activation of the mitogen-activated protein kinase pathway. Furthermore, approximately 70% of melanomas have elevated Akt3 signaling due to increased gene copy number and PTEN loss. Therefore, targeting (V600E)B-Raf and Akt3 signaling is necessary to prevent or treat cutaneous melanocytic lesions. Agents specifically targeting these proteins are needed, having fewer side effects than those inhibiting both normal and mutant B-Raf protein or targeting all three Akt isoforms. In this study, a unique nanoliposomal-ultrasound-mediated approach has been developed for delivering small interfering RNA (siRNA) specifically targeting (V600E)B-Raf and Akt3 into melanocytic tumors present in skin to retard melanoma development. Novel cationic nanoliposomes stably encapsulate siRNA targeting (V600E)B-Raf or Akt3, providing protection from degradation and facilitating entry into melanoma cells to decrease expression of these proteins. Low-frequency ultrasound using a lightweight four-cymbal transducer array enables penetration of nanoliposomal-siRNA complex throughout the epidermal and dermal layers of laboratory-generated or animal skin. Nanoliposomal-mediated siRNA targeting of (V600E)B-Raf and Akt3 led to a cooperatively acting approximately 65% decrease in early or invasive cutaneous melanoma compared with inhibition of each singly with negligible associated systemic toxicity. Thus, cationic nanoliposomes loaded with siRNA targeting (V600E)B-Raf and Akt3 provide an effective approach for targeted inhibition of early or invasive cutaneous melanomas.

Applications of ultrasonic skin permeation in transdermal drug delivery.

Transdermal ultrasound-mediated drug delivery has been studied as a method for needle-less, non-invasive drug administration. Potential obstacles include the stratum corneum, which is not sufficiently passively permeable to allow effective transfer of many medications into the bloodstream without active methods. A general review of the transdermal ultrasound drug delivery literature has shown that this technology offers promising potential for non-invasive drug administration. Included in this review are the reported acoustic parameters used for achieving delivery, along with the known intensities and exposure times. Ultrasound mechanisms are discussed as well as spatial field characteristics. Accurate and precise quantification of the acoustic field used in drug delivery experiments is essential to ensure safety versus efficacy and to avoid potentially harmful bioeffects.

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.

Perspectives on transdermal ultrasound mediated drug delivery.

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.

MR thermometry characterization of a hyperthermia ultrasound array designed using the k-space computational method.

BACKGROUND: Ultrasound induced hyperthermia is a useful adjuvant to radiation therapy in the treatment of prostate cancer. A uniform thermal dose (43 degrees C for 30 minutes) is required within the targeted cancerous volume for effective therapy. This requires specific ultrasound phased array design and appropriate thermometry method. Inhomogeneous, acoustical, three-dimensional (3D) prostate models and economical computational methods provide necessary tools to predict the appropriate shape of hyperthermia phased arrays for better focusing. This research utilizes the k-space computational method and a 3D human prostate model to design an intracavitary ultrasound probe for hyperthermia treatment of prostate cancer. Evaluation of the probe includes ex vivo and in vivo controlled hyperthermia experiments using the noninvasive magnetic resonance imaging (MRI) thermometry. METHODS: A 3D acoustical prostate model was created using photographic data from the Visible Human Project. The k-space computational method was used on this coarse grid and inhomogeneous tissue model to simulate the steady state pressure wavefield of the designed phased array using the linear acoustic wave equation. To ensure the uniformity and spread of the pressure in the length of the array, and the focusing capability in the width of the array, the equally-sized elements of the 4 x 20 elements phased array were 1 x 14 mm. A probe was constructed according to the design in simulation using lead zerconate titanate (PZT-8) ceramic and a Delrin plastic housing. Noninvasive MRI thermometry and a switching feedback controller were used to accomplish ex vivo and in vivo hyperthermia evaluations of the probe. RESULTS: Both exposimetry and k-space simulation results demonstrated acceptable agreement within 9%. With a desired temperature plateau of 43.0 degrees C, ex vivo and in vivo controlled hyperthermia experiments showed that the MRI temperature at the steady state was 42.9 +/- 0.38 degrees C and 43.1 +/- 0.80 degrees C, respectively, for 20 minutes of heating. CONCLUSION: Unlike conventional computational methods, the k-space method provides a powerful tool to predict pressure wavefield in large scale, 3D, inhomogeneous and coarse grid tissue models. Noninvasive MRI thermometry supports the efficacy of this probe and the feedback controller in an in vivo hyperthermia treatment of canine prostate.

Glucose measurements with sensors and ultrasound.

Accurate monitoring of the blood glucose level in diabetics is essential in preventing complications. Generally, conventional over-the-counter glucose meters require frequent painful finger punctures to obtain samples, which makes a noninvasive method preferable. The purpose of this study was to demonstrate that glucose levels can be measured transdermally with the combination of the low-profile cymbal array and an electrochemical glucose sensor consisting of amperometric electrodes and a novel glucose oxidase hydrogel. Interstitial fluid glucose concentrations can be determined with the electrochemical glucose sensor after the skin is made permeable to glucose by ultrasound (US) (20 kHz) with the thin (< 7 mm) and light (< 22 g) cymbal array. Using this array to deliver insulin into hyperglycemic rats, our previous experiments demonstrated that blood glucose levels would decrease 233.3 mg/dl with 5 min of US exposure. With the sensor and array, our goal was to determine the glucose levels of hyperglycemic rats noninvasively and evaluate the possible bioeffects. A total of 12 anesthetized rats were placed into two groups (US exposure group and control group) and the array (I(SPTP) = 100 mW/cm(2)) with a saline reservoir operating for 20 min was affixed to the abdomen. The array was removed and an electrochemical glucose sensor was placed on the exposed area to determine the glucose concentrations through the skin. Comparison was made using a commercial glucose meter with the blood collected from a jugular vein. The average blood glucose level determined by the sensor was 356.0 +/- 116.6 mg/dl, and the glucose level measured by the commercial glucose meter was 424.8 +/- 59.1 mg/dl. These results supported the use of this novel system consisting of the electrochemical glucose sensor and the cymbal array for glucose monitoring.

A 63 element 1.75 dimensional ultrasound phased array for the treatment of benign prostatic hyperplasia.

BACKGROUND: Prostate cancer and benign prostatic hyperplasia are very common diseases in older American men, thus having a reliable treatment modality for both diseases is of great importance. The currently used treating options, mainly surgical ones, have numerous complications, which include the many side effects that accompany such procedures, besides the invasive nature of such techniques. Focused ultrasound is a relatively new treating modality that is showing promising results in treating prostate cancer and benign prostatic hyperplasia. Thus this technique is gaining more attention in the past decade as a non-invasive method to treat both diseases. METHODS: In this paper, the design, construction and evaluation of a 1.75 dimensional ultrasound phased array to be used for treating prostate cancer and benign prostatic hyperplasia is presented. With this array, the position of the focus can be controlled by changing the electrical power and phase to the individual elements for electronically focusing and steering in a three dimensional volume. The array was designed with a maximum steering angle of +/- 13.5 degrees in the transverse direction and a maximum depth of penetration of 11 cm, which allows the treatment of large prostates. The transducer piezoelectric ceramic, matching layers and cable impedance have been designed for maximum power transfer to tissue. RESULTS: To verify the capability of the transducer for focusing and steering, exposimetry was performed and the results correlated well with the calculated field. Ex vivo experiments using bovine tissue were performed with various lesion sizes and indicated the capability of the transducer to ablate tissue using short sonications. CONCLUSION: A 1.75 dimensional array, that overcame the drawbacks associated with one-dimensional arrays, has been designed, built and successfully tested. Design issues, such as cable and ceramic capacitances, were taken into account when designing this array. The final prototype overcame also the problem of generating grating lobes at unwanted locations by tapering the array elements.

Short ultrasound exposure times for noninvasive insulin delivery in rats using the lightweight cymbal array.

The purpose of this study is to demonstrate the feasibility of using short ultrasound exposure times to noninvasively deliver insulin with a lightweight (<22 g), low-profile (37 x 37 x 7 mm3) cymbal array (f = 20 kHz). Using hyperglycemic rats, previous experiments using the array demonstrated that blood glucose would decrease approximately 250 mg/dl from 60 and 20 minutes of pulsed ultrasound exposure for transdermal insulin delivery. Using a similar intensity (Isptp = 100 mW/cm2, 20% duty cycle), the goal was to determine if the same effect can be achieved with only 5 minutes of ultrasound exposure. For these experiments, 20 Sprague Dawley rats were anesthetized and shaved, and a 1-mm watertight standoff reservoir that held the insulin or saline was placed between the rat's abdomen and the ultrasound array. At the beginning of the experiment and every 30 minutes, 0.3 ml of blood was collected from the jugular vein to determine the blood glucose level (milligrams per deciliter) for a total of 90 minutes. For comparison purposes 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 without any ultrasound. The second control group had saline in the reservoir with ultrasound operating at Isptp = 100 mW/cm2 for 60 minutes. For the noncontrol experiments, the third group used insulin with ultrasound exposure for 10 minutes. The last group used insulin with ultrasound operating with a 5-minute exposure to examine the effects of using short ultrasound exposure times on delivery. For the 10- and 5-minute ultrasound exposure groups, the glucose level was found to decrease from the baseline to -174.6 +/- 67.2 and -200.4 +/- 43.4 mg/dl measured after 1 hour, respectively. These results indicated that ultrasound exposure times do not need to be long to deliver a clinically significant insulin dose to reduce a high blood glucose level.

Noninvasive ultrasonic transdermal insulin delivery in rabbits using the light-weight cymbal array.

OBJECTIVE: Recent studies have shown that ultrasound-mediated transdermal drug delivery offers a promising potential for noninvasive drug administration. The purpose of this study was to demonstrate ultrasonic transdermal delivery of insulin in vivo using rabbits with a novel, low-profile two-by-two ultrasound array based on the cymbal transducer. As a practical device, the cymbal array (f = 20 kHz) was 37 x 37 x 7 mm3 in size and weighed less than 22 g. Using the same array on hyperglycemic rats, our previous experiments demonstrated that blood glucose would decrease 233.3 +/- 22.2 mg/dL in 90 min from 5 min of pulsed ultrasound exposure. With a similar intensity (Isptp = 100 mW/cm2, 20% duty cycle), our goal was to determine if the same effect could be achieved with rabbits. METHODS: Experiments were performed in 16 New Zealand White rabbits (weighing 2.7-3.4 kg) divided into three groups: two controls and one ultrasound with insulin exposure. The rabbits were first anesthetized, and their thigh area was shaved for the exposure area. While the animal was lying in the lateral recumbent position, a 1-mm-thick, water-tight standoff (reservoir) that held insulin or saline was fastened between the thigh and the ultrasound array. The first control group (control 1: insulin-no ultrasound) had insulin placed in the reservoir with no ultrasound exposure, while the second control group (control 2: saline-ultrasound) had saline in the reservoir with ultrasound operating at Isptp = 100 mW/cm2 for 60 min. The third rabbit group (ultrasound-insulin) was subjected to insulin with ultrasound exposure for 60 min (Isptp = 100 mW/cm2). At the beginning of the experiment and every 15 min for 90 min, 0.3 mL of blood was collected from the ear vein to determine the blood glucose level (in mg/dL) using a glucose monitoring system. For comparison between individual rabbits, the change in the blood glucose level was normalized to a baseline value. The insulin reservoir was removed with the array after the ultrasound was turned off at 60 min of exposure. RESULTS: For both controls, insulin-no ultrasound and saline-ultrasound, the blood glucose level varied from the initial baseline by approximately +75 mg/dL. However, for the ultrasound-insulin group, the glucose level was found to decrease to -132.6 +/- 35.7 mg/dL from the initial baseline in 60 min. Even after the array and insulin reservoir were removed, the blood glucose level of ultrasound-insulin group continued to decrease to -208.1 +/- 29 mg/dL from the initial baseline. CONCLUSIONS: These results indicate the feasibility of using a low-cost, lightweight cymbal array for enhanced transdermal insulin delivery using ultrasound.

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.

Ultrasound-mediated transdermal transport of insulin in vitro through human skin using novel transducer designs.

Recent studies have shown that ultrasound (US)-mediated transdermal drug delivery offers a promising potential for noninvasive drug administration. The purpose of this study was to improve low-frequency (20 kHz) US methods for enhancing the transport of insulin in vitro across human skin. The feasibility of using US produced by small, lightweight novel transducers was explored for enhancing the transport of insulin across skin. Previous investigators have used US devices such as large, heavy sonicators or commercially obtained transducers for this type of research. The experiments carried out in this study used two low-profile novel US transducer arrays, the stack and standard array, for improved transport of insulin. The stack array generated a spatial peak temporal peak intensity (I(SPTP)) of 15.4 +/- 0.6 mW/cm(2) and the standard array had an I(SPTP) of 173.7 +/- 1.2 mW/cm(2). Spectrophotometeric absorption techniques were used for determining insulin transport in vitro across human skin. Compared with passive transmission (4.1 +/- 0.5 U) over an exposure period of 1 h, the standard array facilitated over a sevenfold increase in the noninvasive transdermal transport of Humulin R insulin (45.9 +/- 12.9 U). Using Humalog insulin with the standard array, there was a fourfold increase in the US-facilitated transmission over that in the control. These promising results indicate that low-frequency US can be used in a practical device for enhanced transport across the stratum corneum.

Transducer design for a portable ultrasound enhanced transdermal drug-delivery system.

For application in a portable transdermal drug-delivery system, novel transducers have been designed to enhance insulin transmission across skin using ultrasound. Previous research has shown transdermal delivery of insulin across skin using commercial sonicators operating at 20 kHz with intensities ranging from 12.5 to 225 mW/cm2. The goal of this research was to design and construct a small, lightweight transducer or array that could operate with a similar frequency and intensity range as a commercial sonicator used in previous transdermal ultrasound insulin experiments, but without the weight and mass of a sonicator probe. To obtain this intensity range, a cymbal transducer design was chosen because of its light, compact structure and low resonance frequency in water. To increase the spatial ultrasound field for drug delivery across skin, two arrays, each comprising of four cymbal transducers, were constructed. The first array, designated the standard array, used four cymbals transducer elements in parallel. A second array (named the stack array) used four cymbal transducers that used stacked piezoelectric discs to drive the titanium flextensional caps. Under similar driving conditions, the standard array produced intensities comparable to those achieved using a commercial sonicator.