Desperate company finds huge opportunity with tiny syringe

Necessity has been called the mother of invention, but the adventures of one Bay Area startup suggest a corollary in biotechnology, desperation can be the father of discovery.

Tom Abate, SF Chronicle Staff Writer

Earlier this year, EndoBionics, an 11-person firm in San Leandro, accidentally discovered an unknown circulatory system that appears to irrigate the outside of the heart — notably the three arteries that nourish the body’s hardest-working muscle.

The discovery, which emerged from studies conducted by Stanford cardiologist Mehrdad Rezaee and UCSF scientist Muhammad Baluom, opens new ways to treat heart disease by using the microsyringe to deposit drugs at pinpoint locations in and around the arteries of the heart.

This promising find recently prompted Medtronic, a large medical device firm with local offices in Santa Rosa, to invest in the startup just as it was running out of cash.

The story of how one desperate company stumbled into a discovery began three years ago, when 23-year-old Kirk Seward entered the Ph.D. program in mechanical engineering at UC Berkeley to study under Professor Al Pisano, an expert in micro-fabrication — i.e., building itty-bitty things.

It so happened that Pisano had recently invented a tiny syringe, thinner and shorter than a single toothbrush bristle. Seward had experience designing catheters — wires that doctors thread through the body’s blood vessels to perform a variety of chores. Cameras, balloons and mini-scalpels had all been attached to catheters. Without knowing exactly what they’d do with a microneedle catheter, the two men decided to build such a device.

Seward started with a standard catheter, consisting of an inner wire about the thickness of a guitar string, wrapped inside protective tubing. Their real innovation was the nifty technique Seward developed to inject and retract the microsyringe.

Imagine a thin, tiny balloon at the end of the catheter wire. The syringe was fixed to this balloon at a right angle. This design ensured that while the catheter was being threaded through the blood vessels, the tip of the syringe would remain inside the protective tubing, so as to not rip the tissue.

Once the catheter reached its destination, the operator could press a hydraulic actuator, engorge the balloon with water and send the needle shooting out through the side of the protective tubing. Releasing the mechanism reversed the flow, allowing the needle to slip back inside the catheter’s outer wrap.

To form a company around this invention, Seward and Pisano contacted Lynn Barr, now 43, who had experience in medical technology development.

With limited backing from friends and angel investors, the former high-tech executive took an unusually cheap route to getting the company off the ground.

Barr conceived the business plan for EndoBionics while guest teaching a biotechnology class at Miramonte High School in Orinda. There, students identified shortcomings in two common treatments for heart disease for which the microsyringe might provide a solution.

We all know the heart pumps blood. But to keep the pump working around the clock, three vital arteries on the heart’s outer surface must deliver it a constant supply of oxygen-rich blood. Heart disease commonly occurs when one or more of these arteries gets clogged. Deprived of oxygen, the muscle dies.

To clear blocked arteries, doctors have developed techniques such as angioplasty, in which a balloon at the end of a catheter is inflated to push open the blood vessel.

To prevent the artery from collapsing after the balloon is withdrawn, stents are used. These wire mesh devices are delivered via catheter and opened,

umbrella-like, to support the blood vessel at its weakest point.

In 10 to 30 percent of cases, a clogging buildup recurs at or near the stent. Scientists theorize that the implant provokes inflammation that restricts blood flow. To combat this phenomenon, biomedical researchers coat the stents with drugs that prevent the buildup.

As Barr explained, drugs on the surface of stents don’t permeate much of the artery wall because the inner lining of blood vessels, called the endothelium, is slicker than Teflon, and nothing sticks. But if EndoBionics’ syringe were to poke through the artery wall, it might get the medicine past the endothelium and outperform drug-coated stents.

The Orinda high schoolers also identified prospective buyers for this theoretical use. A handful of stent makers, including Johnson & Johnson, Boston Scientific, Guidant and Medtronic, are competing to develop better devices for the U.S. market, which is already worth about $3 billion a year. For one of those firms, EndoBionics’ syringe might be a way to leapfrog the competition.

All that was wishful thinking last year, when Barr asked former Chiron scientist Judith Wilber, 55, to design experiments to test whether the theory worked.

Wilber did the first test late last year, loading the syringe with a fluorescent dye and making a single injection into each of the three main arteries of an animal heart to see the percolation pattern.

"We expected to see a little blob of drug," she said. "What we saw instead was that the drug went all the way through the arteries."

This was exciting and unexpected. To corroborate this find, Wilber turned to Rezaee, a Stanford cardiologist who had heard about the microsyringe through the scientific grapevine.

"I was the most pessimistic of the group," said Rezaee. His skepticism turned to excitement as a series of increasingly rigorous tests, aided by UCSF’s Baluom, showed that one or two needle pricks through the arterial wall sent the drug permeating through the entire blood vessel.

Although he still can’t completely explain why this happens, Rezaee offered a theory: Arteries are wrapped in a layer of fat and elastic fibers called adventitia, which function something like the packaging popcorn you might put into a box to cushion a fragile vase.

When the syringe pokes through the artery wall and reaches the adventitia, there is no Teflon coat to prevent the drug from penetrating the artery wall and coating the cells in the entire length and circumference of the blood vessel.

As Wilber and Rezaee expanded their data, Barr presented the findings to venture capitalists, the big stent companies and just about anybody who would listen. Time was of the essence. The company was sputtering out of cash.

"We were described by one of our VC friends as a Ferrari with a one-gallon gas tank," Barr said.

At the end of October, Barr signed a deal with Medtronic to explore uses of the device to treat heart disease. Details are private, but Barr said the terms ensure the company’s survival.

Bill Hawkins, president of the Medtronic division in Santa Rosa that will lead the development, described how excited he was when he first saw the data from Rezaee’s experiments.

"What intrigued me was the phenomenon of the drug being able to wick down the length of the blood vessel," he said. "I thought, ‘This is clearly something we need to be in front of.’ "

Now EndoBionics and Medtronic are back at work, trying to turn these possibilities into products. But elsewhere, scientists at startup firms are playing the same game, racing to make a big find before they run out of cash. Or failing that, hoping their paychecks clear.

On a really good week, they have it both ways.

http://sfgate.com/cgi-bin/article.cgi?file=/chronicle/archive/2002/11/04/BU202293.DTL&type=business