"In the words of my generation, up yours!" -- Russell Casse to alien invaders in "Independence Day"

A tiny camera tucked inside an easy-to-swallow capsule may soon make a big difference in detecting colon cancer early.
I. Hole in Pill Endoscopes' Resume Gets Filled
Ingestible capsule cameras have been around for a little over a decade now.  But while these probes have been authorized by the U.S. Food and Drug Administration (FDA) for inspection of a wide range of other parts of the digestive track -- including the esophagus, stomach, and small intestine -- they still weren't technically authorized to image the large intestine until this week.
Tireless development and a reasonable compromise have at last opened up that gaping hole in the capsule cam's resume, with the approval of Given Imaging Ltd.'s (GIVN) capsule camera technology for imaging the large intestine.  The approval had its limitations (the compromise bit), but it will offer great relief and new disease detection capabilities to some patients.

It is not surprising that Given Imaging was the first company to score FDA approval on the difficult procedure.  Founded in the city of Yokneam Illit, Israel, Given Imaging was arguably the first "inventor" of the pill capsule endoscope.  It began developing the technology in 1998. 

Three years later it wowed the world, scoring FDA approval of its first generation capsule endoscopy technology, dubbed M2A.  Designed to spot small intestinal disorder, the M2A imaging "pill" was the first device of its kind approved for active treatment of patients.  It was detailed in a 2000 paper in the prestigious peer-reviewed journal Nature.

Given Imaging was the first company to commercialize a medical capsule camera.

The M2A -- eventually renamed the "PillCam" -- was a clever application of digital imaging technology to improve a problematic, but necessary medical procedure -- the endoscopy.
II. Endoscopy's First Battle -- Lighting the Tunnel
As early as the eighteenth century, the need to inspect the gastrointestinal tract to diagnose certain medical disorders had already become apparent [source].  The first problem facing physicians was the fact that our digestive tracts are indeed "where the sun [doesn't] shine."
German doctor Philipp Bozzini devoted the later years of his life to trying to find a lichtleiter ("light conductor") capable of safely illuminating the digestive tract for inspection.
A brilliant mind of his time, Mr. Bozzini's hunt for both figurative and literal illumination was cut tragically short when he contracted typhus.  This was before the days of vaccines, so Mr. Bozzini had been working as a "plague physician".  He managed to save the lives of 42 typhus patients under his care in the town of Frankfurt, Germany, but the brilliant doctor was unable to save his own life.  He died at age 36.

Early endoscopes were hard to use and custom-made. [Image Source: Google Books]

Following his death the topic was sometimes discussed, but it would not be until the mid 1800s that physicians became passionate once more about the hunt for gastrointestinal lighting.  Dr. Adolph Kussmaul, another German-born physician, became the first to successfully illuminate the digestive tract in 1868. He performed a risky procedure on a sword-swallower that used a so-called "gasogen" light -- a mixture of turpentine and alcohol.
An emerging technology would soon make lighting practical for those of us that aren't sword swallowers.  The incandescent lamp -- believed to be invented by English scientist Sir Humphry Davy's in 1802 -- became quickly adopted in the late 1880s after Thomas Edison and Hiram S. Maxim's rival firms developed competing carbon-fiber-based electrical lighting products.

Thomas Edison with a bulb
Refinements to the incadescant lightbulb by Thomas Edison (pictured) and others made it a practical solution for illuminating early endoscopes. [Image Source: Getty Images]

German Dr. Theodore Rosenheim in 1904 turned heads when he began using a rectal endoscope to identify colon cancer. Dr. Karl Leo Wilhelm Brünings was another early pioneer, using an illuminated design in 1907 to detect lung disease.  Over the next couple decades, the German technology gain acceptance in the U.S. and Asia, and gradually became commercialized.
III. The Evolution of the Modern Endoscope
Jewish German-born Dr. Brünings -- often called the "father of gastroscopy" -- developed a rubber-tipped model in the 1920s that was widely used worldwide.  In 1933 he was arrested by Nazi party officials [source], but was released in 1934.  He subsequently left for the U.S., where he would continue to be a leading voice and advocate of digestive tract imaging for years to come.
In 1950 Japan's Olympus Corp. (TYO:7733) and University of Tokyo researcher Dr. Tatsuro Uji devised a critical invention, creating the first gastrointestinal camera.  That innovative device was dubbed the GT-I Gastrocamera.

Olympus Gastrocam
Olympus was the first to add the camera to the endoscope. [Image Source: JSME]

But for all the creative ideas and sales progress up until 1970, or so, barium radiography remained a more widespread diagnostic tool than endoscopes.

But in the 1970s and 1980s, the medical community entered into a golden age of endoscopy.  Unlike passage testing with radioactive tracers -- which carries minor cancer risks and isn't very accurate -- endoscopy was safe and effective.  But some problems still remained.  Namely, it wasn't very comfortable.

Endoscopy became a leading diagnostic procedure in the 1970s. [Image Source: NCI]

On the mouth-side you were fighting gag reflexes, requiring patients to sometimes be sedated during procedures.  On the other end researchers had to resort to tricks such as inflatable scopes or pressurizing the intestines with air to fight the powerful muscle contractions and any blockages of fecal matter.  The result, as one might expect, was a lot of discomfort for the patient.
It wasn't until Given Imaging came along in the late 1990s that a less unpleasant alternative arrived.
IV. A Race to (or Through?) the Bottom
Japan and Israel were the early leaders in the high-tech new twist on the endoscope.  With Given Imaging's 2001 commercial launch of the M2A (PillCam), the race was on.

Pillcam Gen 1
A teardown (top) of the first-gen PillCam and a schematic of it.
[Image Source: (top), bottom (Given Imaging)]

By late 2001 Japan's RF Comp., Ltd. (founded in 1998 by Jiro Maruyama) had released a competitor device, the NORIKA3.  The NORIKA3 one-upped the M2A in that it generated its own power via turning the jostling of digestion into power for the onboard microelectronics, via a small onboard generator. 

RF Comp.'s camera pills are powered by biomechanical generators.
[Image Source: Medi-Nation]

The race for the best pill camera was on.  In 2004, Given Imaging became the first to receive FDA permission to use a capsule solution to image the esophagus.
In 2005, RF Comp., Ltd. debuted its second generation capsule endoscope, dubbed "Sayaka", which recorded high resolution 2 MB/mm2 resolution images for a mosaic model of the small intestine.  Two years later Given Imaging announced its own next generation solution, the PillCam SB 2, which achieved FDA approval in mid-2007.  It followed the next year with a pH-sensing capsule, using technology it acquired with the purchase of startup Bravo pH Monitoring.

RF Comp. released its second generation Sayaka capsule in 2005.

By May 2009, Given Imaging had sold its millionth Pillcam, but it was still struggling to achieve FDA approval for colon imaging.  That meant physicians were still doing things "the old fashioned way" -- a rude annoyance for patience.

The Given Imaging Pillcam has been used on over 2 million patients to date.
[Image Source: Reuters]

The key problem was that compared to the esophagus or small intestine -- narrow tubes -- the large intestine was cavernous and highly folded.  Hence pillcams were unable to deliver as good results as traditional procedures, which "inflated" the intestine, exposing any potential cancerous growths that might be hiding unseen in folds.
V. Concession Plows Path to Approval
Given Imaging eventually conceded that this problem likely wasn't solvable.  But it determined that there still was a viable market.  In the U.S. alone it estimates that 750,000 people a year are unable to undergo traditional endoscopy for various reason including anatomy issues, previous surgery, or various colon diseases.
The Israeli company proposed a compromise.  It would stop trying to push its product as an alternative to traditional endoscopy in patients who could undergo that procedure, and would solely market to those who had experience "incomplete endoscopy" -- essentially cases where the procedure was attempted but was too painful or otherwise determined to be medically infeasible.

The FDA was receptive to the new approach.  With the approval, experts estimate that by 2019 the new PillCam may do $60M USD annually in North American market penetration alone.
The brand new model -- PillCam COLON -- is based on the current third generation PillCam platform.  An early second generation-based model was documented in the peer-reviewed Journal of Gastrointestinal Endoscopy in 2011.  The capsule typically takes about eight hours to pass through the large intestine, snapping pictures at up to 4 frames per second.  Its internal circuitry is attached to a smart ASIC that adjusts the frame rate up to 6 fps if it detects that it's travelling faster than expected.
PillCam Clon
PillCam COLON is the first capsule cam approved for imaging the human colon.

Images from the CMOS sensor are relayed via a wireless link made by Ottawa, Canada-based Zarlink Semiconductor Inc.  While some competitors like RF Comp., Ltd. are powered by internal generators, Given Imaging remains convinced that a more affordable and effective solution is simply to use a battery.  For that reason the capsule is a bit bigger (at 11x31 mm), but should also be more reasonably priced.
A number of competitors exist on the market today [source], but thus far Given Imaging's PillCam COLON is the only one to receive FDA approval for imaging the large intestine in any application, although its authorization is limited to patients with an incomplete endoscopy history.

Pill endoscopy competitors
A survey of pill endoscopy providers [Image Source: Yonsei University]

Given Imaging is in the midst of a major business shift, with Irish device firm Covidien plc (COV) announcing a definitive agreement to purchase the Israeli camera pill-maker in December.  The Irish firm is paying close to a billion dollars -- $860M USD -- for the capsule imaging pioneer.
VI. The Next Big Thing -- Japan's Eel Like Anal Capsule
The next big thing in capsule imaging could be next generation models capable of selectively "swimming" into the intestinal folds that typically go unseen with current probes.
Ryukoku University and Osaka Medical College in 2011 announced the creation of a battery-powered capsule dubbed "Mermaid" that could swim in the intestines for eight to ten hours via a flapping tail.

Mermaid Capsule
The "Mermaid" capsule can swim around in the large intestine like an eel. [Image Source: AFP]

That device is currently undergoing testing in humans.  If it works, it could allow capsule imaging to completely replace traditional endoscopy procedures, adding a resounding closing note to centuries of progress.

Given Imaging is also evaluating similar powered propulsion technologies, but has not yet announced any products.

ARM Holdings Plc (LON:ARM) also is making waves in the booming new medical microelectronics market, with its Cortex-M0 processor design, which squeezes smartphone-like processing power into a tiny power-efficient chip.  Likewise Intel Corp. (INTC) is targeting this market with its low-power Quark x86 SoC.  It wouldn't be surprising to see future pillcams drop ASIC solutions and go with either of these new cores.

Source: Given Imaging on Presswire

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