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Several companies are actively working on technologies to improve blood sugar testing and thereby capture a share of the two- to three-billion dollar blood sugar testing market. The goal is to make testing easier, more convenient and, the hope of many, continuous without sticking the finger. Here are some of the companies trying to become the first to offer improved testing and how they plan to do it:
"It's clear that all current sensor development seems to be moving in the same general direction, regardless of the application. There's a deceptively short shopping list of requirements for the next generation of sensors. We think the next generation sensor technology must meet the following requirements, and the current technology fulfills none of them:
"Solutions based on optical signal measurement seem to hold much more promise, but the key problem seems to be those of power and sensitivity, and the seemingly inescapable trade-off that exists between them"
—Andrew J. Barrett of Sensors For Medical Science.
The long-term goal for glucose test technology is to take humans out of it by developing a closed loop system that both tests and then adjusts insulin delivery based on the results. None of the companies mentioned above has a closed loop system yet, i.e., they do not deliver insulin based on the readings they gather. Although MiniMed is probably closest to this capability, any closed loop device will require extensive testing for FDA approval. For now you are still the person responsible for controlling your readings!
All of the devices above measure glucose in interstitial fluid (ISF), the relatively clear fluid that surrounds cells. Glucose moves first from blood vessels through the interstitial fluid, then into cells. The glucose present in interstitial fluid is about 15 to 20 percent lower than glucose in blood. Measuring glucose in a fluid with a different normal range is likely to be confusing for many. Users will be required to sort out the jargon between blood glucose measurements, ISF measurements (about 15 percent lower) and serum levels measured at the lab (about 10 percent to 15 percent higher). This difference may cause some confusion as people adjust to the lower ISF glucose reading, especially if individuals vary in the adjustment factor required. One standard correction factor may not work for everyone nor work in all circumstances.
ISF glucose also falls earlier and rises later than blood glucose. These time differences may be unimportant, except that a 15 or 20 minute delay in the ISF reading may make it more difficult for a closed loop system to be built. They also might cause some uneasiness as a person experiencing a low blood sugar waits for his meter reading to rise. As the sugar rises, readings from the interstitial fluid will lag behind the blood sugar.
Advocates of interstitial testing say that the ISF value is important because this is what cells are actually dealing with. However, it is not clear that the levels of glucose in interstitial fluids surrounding the brain, the most important organ, will change at the same rate as that in less important tissues like the wrist or fingers where these devices will be used. Glucose in fluids surrounding the brain may change at the same pace as it does in the ISF in the fingers, but it will take some time to sort out any differences in how ISF readings really work.
MiniMed has already conducted clinical trials of its sensor and submitted the results to the FDA for approval in December, 1997. A design that's similar to an insulin pump infusion set, their Teflon catheter, instead of delivering insulin, has a small sensor at its tip. It is inserted through the skin and reports out via a small wire to a sensor worn on a belt or elsewhere.
MiniMed has an advantage in this technology since their device can give readings as often as every three to five minutes around the clock. This allows glucose patterns to be rapidly determined so a drop or rise can be more quickly corrected. It also allows rapid identification and correction of problematic blood sugar patterns. In clinical trials, people with type 1 diabetes appeared to be able to correct erratic readings in as little as five to seven days.
MiniMed can be reached at (800) 933-3322.
Sensors For Medicine, Inc.
Scientists today use fiber optics and lasers to measure chemicals in large, bench-top spectroscopy configurations that cost tens of thousands of dollars. Arthur Colvin of SMSI compares current spectroscopy to using a flashlight to find out what's dissolved in a bucket of water. "Scientists shine the light down through the water, and measure changes in the light when it bounces back out. It's not very efficient, because they can recapture only a tiny fraction of the light."
To compensate, you have to find an extremely powerful light source or invest in more sensitive light-measuring equipment. Colvin's innovation is to drop both the flashlight and the light-measuring equipment into the bucket. "This way, light has to travel inches instead of feet," says Colvin. "That means you can use cheaper, less powerful lights and measuring equipment and still get much better results."
SMSI is attempting to do this. Their new oxygen sensor prototypes use a tiny light emitting diode (or LED) as the light source, and an ordinary photodiode, like the ones in solar powered calculators, to measure the light. Both are widely available and cost only pennies apiece in quantity. The vanishingly small size and cost of the components open the door to new applications, like tiny sensors that can be implanted under the skin. SMSI is working on a sensor so small it could be injected into the fatty layer below the skin to measure blood sugar levels.
"If you understand how light behaves in the presence of certain compounds, you can use light to detect the presence or absence of those compounds," says Arthur Colvin, the scientist who designed and patented the SMSI sensor platform. "The hard part is using what you know to build a sensor that's stable, very sensitive and inexpensive." As envisioned, their device would be an extremely tiny light-emitting diode near a separate photodiode receiver.
Between the two would be the ambient ISF glucose and some theoretical molecule that fluoresces in the presence of glucose. The more glucose, the more (or less) fluorescence which is then measured by the photodiode with a signal transmitted to the outside.
Many hurdles remain, such as the development of miniaturized and reliable hardware, the discovery of suitable fluorescent molecules that will fluoresce over the desired measurement range for glucose, stabilization of the fluorescent particle within the hardware and ability to transmit the measured fluorescence measurements outside the body without a significant increase in size or power requirements. There are many questions, like what metal or plastic materials will be involved and will they be simply left under the skin or removed when no longer working. Also, this concept will float or sink on whether a fluorescing molecule that is non-toxic can be found that would work over the desired glucose range. But the approach remains quite interesting.
Synthetic Blood International
This implantable blood sugar detector is designed to be self-refueling from oxygen drawn from the surrounding tissue to refuel the sensor. Theoretically, this would allow glucose readings to take place over a long period of time. The company believes the sensor and battery life may be extended to at least two years.
Oxygen, glucose and enzyme electrodes, developed and patented by Dr. Clark at SBI, are used worldwide. New patent applications covering this sensor include a titanium encased battery and microprocessor, a silicone-sheathed platinum electrode and a glucose oxidase enzyme system enclosed in a semipermeable cellophane acetate membrane. All components in contact with body tissue are widely used in in vivo or implantable medical devices, and the overall design is similar to implantable pacemakers.
The biosensor will be implanted subcutaneously to measure ISF glucose. Potential implant problems are avoided by not having the sensor tip in long term contact with blood in a blood vessel. SBI projects an implant life of up to two years. The implanted biosensor will communicate with an external, wearable receiver that displays and records calculated blood glucose levels on demand or according to a programmed schedule. SBI says it plans a second generation, closed-loop device for use with insulin pumps, but it is not known if they have discussed these plans with either of the major insulin pump companies.
Synthetic Blood International (aka, Implanted Biosystems, Inc.) can be reached at (937) 298-6070.
This company has taken a different approach. Using an approach similar to today's meters, it measures small amounts of interstitial fluid by placing a 1.4 mm hole in the dermis to obtain a sample. No blood is drawn which causes far less pain than today's lancets.
Some have expressed concern that water-based activities like swimming or dishwashing might dilute the ISF glucose because the depth of the hole is so small. However, this is not likely to be a problem unless the user is retaining fluids due to congestive heart failure or kidney failure, or is dehydrated due to inadequate fluid intake or ketoacidosis.
Integ's device is pressed against the skin on the forearm (less sensitive than fingertips) for less than 30 seconds to obtain a reading. A small, hollow lancet collects a tiny drop of interstitial fluid to obtain the reading.
In a research study at the Mayo Clinic, the device was used to test people with a range of glucose levels. They found the dermal ISF results closely tracked blood results.
Integ isn't making any predictions about when its device will be ready to submit to the FDA (the company did that early in 1997, then missed the date and its stock tanked). But Integ still hopes it will hit the marketplace in 1998. Integ plans to sell the meters at Wal-Marts, Kmarts and drugstores, just as the top four manufacturers of existing blood glucose monitors do. It intends to target prices for more expensive, top-of-the-line models, about $250.
SpectRx is also developing a less painful alternative to conventional blood glucose meters.
Unlike Integ's small lancet, their technology uses a tiny laser to create a micropore opening in the skin through which interstitial fluid is collected and measured for glucose. The micropore technique includes a self-regulating feature to insure no damage occurs to viable tissues beyond the outer layer of dead skin cells.
Research by SpectRx also shows a direct correlation between glucose in the ISF and blood. In-house clinical studies conducted by SpectRx have shown that glucose in pure ISF can be measured with existing, off-the-shelf glucose test strip technology.
The SpectRx personal glucose monitoring technology has been licensed to Abbott Laboratories, the world's leading in vitro diagnostic company. Product availability in the U.S. will depend on FDA marketing approval.
Technical Chemicals & Products
The TD Glucose Monitoring System uses a disposable patch on the skin to sample interstitial fluid which is read by a small hand-held monitoring reflectance meter. This meter also measures ISF glucose.
The TD Glucose patch is estimated to be the size of a 5-cent coin and packaged in a pouch that also serves as a means of disposing of the used patch. The patch is single-use, and draws glucose from the ISF in the body through the skin by a mechanism that is not described. Once drawn to the patch, glucose interacts with the company's patented membrane.
However, the patch must be on the skin for about five minutes before a reading can be taken. A tab is then removed from the TD Glucose patch and the "blood" glucose measurement is obtained by placing the TD Glucose meter on the area of the patch where the tab was removed. Technical Chemicals & Products says the retail price of the TD Glucose Monitoring System is expected to be competitive with conventional blood glucose monitoring systems.
This company has only a few routine products available in the United States, such as a urine glucose test and pregnancy tests. Several other products, many related to drug detection, are sold in other countries. Even if the cumbersome, five-minute delay can be overcome, the company is already burdened by its involvement in a very large number of clinical trials on a wide variety of other testing and diagnostic products.
Boehringer Mannheim of Argentina is involved in other company products but the TD Glucose system is still looking for a major player. Their skin patch may suffer from some of the same problems as Cygnus, related to breaking the protective skin surface.
Technical Chemicals & Products, Inc. is located in Pompano Beach, Florida and can be reached at (954) 979-0400.
Cygnus has been working on their GlucoWatch for several years. Cygnus has been trying to develop quick, convenient glucose measurements through the skin. The product name, GlucoWatch comes from their attempt to reduce the required technology to the size of a wristwatch. However, shrinking the original refrigerator-size device to the size of a glucose-sensing wristwatch has proven to be difficult.
This device alters normal skin so that glucose can be leeched out and measured outside the body. Normal dermis does not allow glucose to leak out. But the skin can be forced open by electrical stimulation, chemicals, applying a vacuum or a combination of these approaches, provided that dermal damage is kept to a minimum.
The GlucoWatch operates by applying an electro-osmotic current to the skin. The current opens pores in the skin through which glucose can travel. A similar technology has been used to deliver pain medications through the skin into joints in sports- and other injuries. But pulling glucose out through the skin and measuring it, is far more complicated.
Cygnus had previously developed a patch containing saline solution, called a GlucoPad. This is applied to the outside of the skin to absorb glucose and provides a medium to measure average glucose levels over a period of time.
Unfortunately, the saline solution that absorbs glucose above the abraded skin also provides an ideal setting in which to grow bacteria or fungi. The skin's primary job as a protective barrier is overridden by this device, raising concerns about infection. If an antibiotic is required to prevent infections, constant use of one antibiotic could encourage overgrowth of drug-resistant bacterial strains.
Viruses with their smaller size could present even greater problems. Fortunately, HIV and many other viruses do not survive for long in the open environment. This unit has been designed to provide an enclosed environment that prevents unwanted access.
Problems with skin breakdown is also a concern. Some testers have reportedly had skin discomfort after only 24 hours of use, and it is not known how long one site can be used nor how much recuperation time is needed between uses.
Another major problem is that the wearer cannot measure their glucose during any significant sweating. When sweat glands open up due to heat, hypoglycemia or exercise, this device cannot accurately measure glucose. Size also remains a problem. Although miniaturization is underway, the device is still significantly larger than the average wristwatch.
Craig Carson at Cygnus said in early 1997 that the company planned to file a 510K application with the FDA for approval late in 1997, but no 1997 submission occurred. This technology appears to need several breakthroughs to proceed. Several years may pass before the original vision of the GlucoWatch becomes reality.
Costs of the device are uncertain because the research costs needed to bring this technology to market are vague. Cygnus originally estimated $50 million to $100 million to bring a watch to market. Ongoing costs for the GlucoPad and the saline solution that are replaced daily will add to costs with this approach.
Cygnus got a financial boost in its efforts in June, 1997, when Becton Dickinson promised additional development funds in exchange for marketing rights. BD also provided significant funds for initial development costs.
Cygnus, Inc., can be reached at (415) 369-4300.
Bioject Medical Technologies
Bioject Medical Technologies announced in October, 1997, that it had established a joint venture with Elan Corporation for the research, development, and commercialization of a continuous glucose level monitoring system.
Their patch-like sensor may be coupled to a wrist watch-type monitoring device to measure glucose levels on a 24-hour basis. Their sensor requires changing once a day. Human clinical trials are expected to begin in "early 1998."
Michael Sember, Elan's vice president of planning, investments and development, and a member of Bioject's board of directors said: "With Bioject, we can collaborate with a strong U.S.-based partner to bring our glucose monitoring technology successfully to market. We believe the continuous glucose monitoring system we are developing has tremendous market potential. In contrast to most products in the marketplace, our ambulatory system will provide a disposable skin patch-like sensor that is patient-friendly, minimally invasive, easy to use _ coupled with a lightweight monitoring device.
"In addition, by providing accurate information on a real-time basis at considerably less effort, our continuous system is likely to foster better monitoring. Better monitoring and glucose management can help patients avoid the worst complications of diabetes. We anticipate that our product will be competitively priced accounting for the enhanced performance it will provide over existing technologies in the marketplace." Details on this optimistic technology were not immediately available.
John Walsh, PA, CDE, co-founded Torrey Pines press and co-authored Stop the RollerCoaster and Pumping Insulin with Ruth Roberts, MA. They can be reached at (800) 988-4772 or on their website: http://www.diabetesnet.com.
This article was reprinted with permission from Diabetes Services Inc. — Diabetes Services Inc.