Taking the Sting Out

The fear and discomfort associated with injections rank high as a medical misery. With the FDA approval of a new device called SonoPrep, however, needle pricks for insertion of IVs lines, catheters, and other procedures will lose much of their sting.

Developed by Sontra Medical (Franklin, MA), SonoPrep harnesses low-frequency ultrasound to bring about rapid permeation of the skin, allowing topical anesthetic creams to take effect in just 5 min. What's more, future applications of the same basic technology could include pain-free delivery of vaccinations and monitoring of glucose levels in diabetics.

"The biggest strategic challenge we have is focus," says Tom Davison, Sontra president. "We now have approval for the first application of our product platform—use in topical anesthesia—but there are so many other opportunities for this technology."

Pathways for Treatment

While anesthetic creams have been widely used to reduce pain from needle sticks, it can take up to 60 min to take effect. Waiting for the anesthetic to take effect raises the anxiety level for patients and reduces the productivity of medical personnel, who need to make a second visit to the patient to start an IV or other procedure. By contrast, SonoPrep allows nurses and other clinicians to administer the anesthetic and perform the medical procedure in one short visit.

Building on ultrasound skin permeation technology developed in the 1980s by Robert Langer and Joseph Kost at MIT's Chemical and Bioengineering Laboratory, SonoPrep consists of:

In a typical IV procedure, for example, the clinician first places an adhesive-backed target ring on an area where the needle for the IV line will eventually penetrate the skin—usually on the patient's hand. After powering up the SonoPrep system, the clinician then places the hand piece over the target ring and pushes down to release the coupling solution and activate the ultrasound horn. Meanwhile, the patient holds the return electrode, which measures the increase in skin conductance. As the ultrasound energy transfer occurs, the hand piece emits a slight hissing noise, and the patient feels a tingling sensation. The device automatically shuts off, based on a drop in skin impedance.

For the average patient, the entire ultrasound procedure takes just 15 sec and affects an area of the skin measuring less than 1 cm2. The clinician then wipes off any remnants of the coupling medium, applies a topical anesthetic cream—lidocaine—and covers the target area with a patch. In 5 min, the clinician removes the target rings and inserts the IV catheter.

Unlike ultrasound used in medical imaging, the SonoPrep device operates at a relatively low frequency. The ultrasonic horn contained in the hand piece vibrates at 55,000 times per second (55 kHz), which creates cavitation bubbles that expand and contract in the coupling medium. This in turn disorganizes the lipid bilayer of the stratum corneum—the outer layer of the skin—and creates tiny microchannels that serve as pathways for delivering drugs or for extracting bodily fluids for analysis. The process is also reversible: Skin in the treated area returns to its normal state within 24 hrs.

Solving the Challenges

What is now a commercial product is the result of many years of work, both at MIT and Sontra Medical. Langer and Kost did the fundamental scientific work, which focused on determining the right frequencies that would trigger the cavitation process. But it fell to the engineers and scientists at Sontra to refine this basic work, design a commercial product, and get it approved by the FDA.

"The original sonophoresis protocol conducted at MIT wasn't well suited for commercialization," recalls electrical engineer Scott Kellogg, Sontra's VP of R&D. "The skin pretreatment process took more than an hour, with lengthy skin hydration and ultrasound steps."

Not only did Kellogg and his team need to control the highly chaotic phenomenon of cavitation on skin, but they also had to transform Langer's large, laboratory-style bench top equipment into a compact, battery-operated device. But before all this could be achieved, the engineers first needed to fully understand the underlying technology. This involved a large design of experiments process in which they sought to optimize key ultrasound parameters, such as amplitude, frequency, coupling fluid, and geometry of the ultrasound hand piece.

In this work, the engineers took whatever off-the-shelf power supply equipment they could find and adapted their own acoustics to them. The engineers also needed to develop a way to control the "dose" of ultrasound applied to the skin since the permeation process varies from person to person.

The solution to this problem: Inventing a feedback mechanism—the patient electrode—in which a small current is passed through the body so that changes in impedance can be measured while ultrasound is being applied. The end result is a system that automatically terminates the procedure at the precise time that ultrasound breaches the stratum corneum.

CEO Davison, himself a Ph.D. in physiology, also challenged the engineers to fully understand the effect of ultrasound on the skin. With the help of Dr. Rox Anderson and his team at Wellman Labs at Massachusetts General Hospital in Boston, the engineers employed such tools as laser microscopy, dyes, and histology. This work gave them valuable benchmark information to optimize their designs.

Hands-On Work

Armed with a deeper knowledge of the fundamental technology, the engineers progressed to the hands-on work of designing a commercial prototype. Kellogg himself built the early circuitry, using OrCAD for schematic design and MP LAB to program the Microchip PIC processor in the control system. Microchip also provided an evaluation board used in the first-generation design to support the software and drive the battery-operated ultrasound circuit board.

Among other valuable tools, Kellogg turned to COSMOS finite element analysis software to develop the system's acoustic transducer. National Instruments' LabView, together with bench top equipment, helped to capture impedance data essential for the design of feedback algorithms that determine when the skin permeation is complete. And TechEn, an engineering consulting firm in Milford, MA, worked with Kellogg to refine the early electronic designs for manufacturability, including PCB layouts and conversion of programming software to C.

On the mechanical side, Sontra built the first prototype hand piece and tackled the design of the plastic cartridge containing the coupling solution.

Design consultants also played a big role. For instance, Product Genesis (Cambridge, MA) used Pro/ENGINEER to refine the early designs of the hand piece, particularly the fluid delivery system for the coupling solution. Design Access (Milford, MA) took that design and made further recommendations, especially on ergonomics. For prototypes of the hand piece, the team provided SolidWorks models to Quickparts.com, which used the data to generate parts via stereolithography. Visual Engineering (Austin, TX) did rapid prototypes of parts requiring more precise tolerances. Among other key suppliers, the engineers found Blow Molded Specialties in Providence, RI, which makes the ABS cartridges for the coupling solutions.

Relief for Caregivers

All these design efforts have resulted in a technology that is receiving an enthusiastic response at the clinical level. "The device appears to be having very good success in pediatrics, which is always a major area of concern for us," says Debbie Benvenuto, an IV nurse who is education manager for the Infusion Nurses Society, Norwood, MA.

Sontra's 510(k) submission to the FDA was supported by clinical data from studies covering 500 patients at such facilities as Boston's Brigham & Women's Hospital and Rhode Island Hospital in Providence. These studies showed that ultrasound treatment with SonoPrep, together with application of a topical anesthetic cream, resulted in a rapid onset of cutaneous anesthesia—and a virtually painless insertion of catheters for most patients.

Katherine Dickinson, Sontra's director of Clinical Studies, adds that the company will continue to perform more studies in which SonoPrep is used in other needle procedures besides IVs, including immunizations, central catheters, and port access for oncology patients receiving chemotherapy. Sontra is pricing the SonoPrep device at $2,000, says Marketing VP Barry Marston.

Using SonoPrep in topical anesthetic applications—said to be a $100 million annual market—is just the tip of the iceberg, says CEO Davison.

Sontra also sees far-reaching potential in applying the SonoPrep process in reverse—that is, using it as a noninvasive method for drawing out body fluids for analysis. The company has already developed and begun clinical tests of its own biosensor, which patients would apply to their skin for continuous glucose monitoring—a $5 billion dollar worldwide market. Rather than the annoying finger-prick tests that most diabetics must endure to monitor blood sugar levels, the sensor would transmit glucose data wirelessly to a meter.