title: Noninvasive ultrasonic transdermal insulin delivery in rabbits using the light-weight cymbal array.
abstract: 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.
authors.affiliation: Department of Bioengineering, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Seungjun
authors.initials: S
authors.lastname: Lee
authors.forename: Benjamin
authors.initials: B
authors.lastname: Snyder
authors.forename: Robert E
authors.initials: RE
authors.lastname: Newnham
authors.forename: Nadine Barrie
authors.initials: NB
authors.lastname: Smith
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D007260:Infusion Pumps; D007328:Insulin / Q000008:administration & dosage* / Q000494:pharmacology; D023421:Models, Animal; D011817:Rabbits; D014465:Ultrasonics
chemical_list: D001786:Blood Glucose; D007328:Insulin