BB&T Contributing Editor

DUSSELDORF, Germany – The medical device market in Europe encompasses a diverse range of products offered by suppliers from all regions of the world, making it one of the most competitive arenas of the global market. The annual MEDICA trade fair, presented by Messe Düsseldorf in mid-November, provided a forum for exhibition of the latest medical products offered by 4,190 companies from 66 countries, and attracted a record number of exhibitors.

Trends in the medical device industry are positive, with strong interest on the part of physicians and other healthcare professionals in products that offer more efficient diagnosis and therapy, and thereby help address continued pressures to control health care costs.

Important new developments were announced in the area of diabetes management technologies, addressing a growing public health problem in essentially all developed regions of the world that is now becoming a significant issue even in less developed countries. New products for use in remote monitoring of patients, as well as for point-of-care (POC) testing, were introduced at the exhibition that address the growing need for technologies that allow healthcare to be delivered in lower-cost settings, and with greater efficiency.

Image-guided therapy was another area showcased at the MEDICA meeting, including products for use in endoscopic procedures as well as advanced imaging modalities that allow pathological analysis of tissues to be performed during a surgical procedure.

As shown in Table 1 on the following page, the global medical device market is estimated at $193 billion in 2004, growing to $210 billion in 2005. The market is projected to grow at a 7.5% compound annual rate through 2009, making it one of the more attractive segments within the global economy. Furthermore, certain segments (e.g., implantable cardioverter defibrillators, drug-eluting coronary stents, neurostimulation devices, orthopedic implants and molecular diagnostic products) are expected to grow at rates approaching 20% and higher.

Advances in diabetes management

The continued expansion of the market for products used in diabetes management, driven primarily by the growth in worldwide prevalence of diabetes, continues to attract new competitors, and to drive development of new testing technologies. As shown in Table 2, the market for whole blood glucose testing products is expected to exceed $6.7 billion in 2005, and is projected to grow at double-digit rates throughout most of the remainder of the decade. DiaMatrix Ltd. (Basingstoke, UK) exhibited a new biosensor technology at the MEDICA exhibition that can be used for whole blood glucose monitoring, as well as for monitoring of blood lipids such as total cholesterol, HDL and LDL cholesterol and triglycerides, and for immunoassays such as HbA1c. The key advantage of the DiaMatrix technology is low cost. Sensors are fabricated on a paper substrate using screen-printing techniques. Multiple test strips can be fabricated on a single substrate, and a wide variety of device components can be created including internal sample wells and flow-through reaction chambers.

The company has developed a prototype of a paper glucose sensor that could be well-suited to the market in developing countries, and a patent has been filed on a new glucose meter concept that allows screening for diabetes as well as for elevated cholesterol with a disposable sensor that is linked to the Internet. The latter device is targeted at the market for home screening for pre-diabetes, in order to identify the millions of individuals worldwide who are developing diabetes but have not been diagnosed, and who would benefit from earlier initiation of therapy. DiaMatrix is in discussions with potential partners to commercialize the technology for diabetes applications.

Numerous suppliers of blood glucose meters from Taiwan and Korea exhibited new products at the MEDICA conference, demonstrating the emerging impact of low-cost suppliers on the glucose testing market. TaiDoc Technology (Taiwan) exhibited the CleverChek, a combination blood glucose meter and blood pressure monitor that also includes voice readout for the visually impaired. Pending receipt of a CE mark and FDA clearance, the CleverChek will be launched in Europe and the U.S. at a price of $42, a fraction of the reimbursement amount provided by Medicare in the U.S. ($450 for a meter with voice capability). The meter performs a test in seven seconds using 0.7 microliters of whole blood.

i-Sens (Seoul, South Korea) also is developing a combination glucose meter and blood pressure monitor that it expects to launch in Europe in 2006 pending receipt of a CE mark. The company will also submit the product for FDA marketing clearance in the U.S. in 2006. The meter provides a result in 5 seconds using 0.5 uL of blood, and employs a laser lancet for reduced medical waste and increased user convenience. i-Sens also is developing a combination glucose meter and cellular phone that will offer increased convenience for diabetics when sending test results to their physician.

Other manufacturers of low-cost glucose meters entering the market in Europe include Infopia BioTechnology (Hsinchu City, Taiwan), with the EasyPlus meter; General Life Biotechnology (Taipei Hsien, Taiwan), with the BeneCheck Plus system for monitoring of glucose, uric acid and total cholesterol; Hangzhou Bravo Technologies (Hangzhou, China), with the Vectra blood glucose meter; Sand County Biotechnology (Hsin-Chu, Taiwan), with the Palm Lab and Palm Lab Micro meters; and Isotech Co. Ltd. (Daejeon, Korea), with the Laser glucose monitor that incorporates a built-in laser that provides blood sampling (0.5 uL) with reduced pain and eliminates the need to handle lancets.

A unique new system for glucose testing, that represents a next-generation system in that it combines sampling and testing in one device, was described by Pelikan Technologies (Palo Alto, California). Pelikan is a developer of a new lancing technology that employs an electronically actuated microneedle with a diameter of 300 micrometers. In December 2004, Pelikan acquired Inventus BioTec, a company that had developed a glucose biosensor technology called GlucoSens. Pelikan now is developing an integrated system consisting of its electronic lancing technology and the GlucoSens biosensor that will perform blood sampling and glucose measurement in a single operation, eliminating the need for the user to handle a separate lancet. In addition, the lancets and sensors will be configured as 50-test disks that are integrated within a compact meter that is about the size of an Apple iPod. The sensors require only 4 nanoliters of blood to perform a measurement, and can complete a test in 4 seconds. The integrated system will be the first to combine lancing and testing in a single device. Product launch is targeted for 2007.

Glucon (Boulder, Colorado) and KMH Co. Ltd. (Gyeonggi-Do, South Korea) exhibited prototype non-invasive glucose monitors at the MEDICA meeting. Glucon, a company founded in 2000 by two Israeli scientists, is developing the Aprise non-invasive glucose monitor, which employs photoacoustic technology. The Aprise system consists of a sensor attached to the skin that is connected via a wireless interface to a hand-held meter that displays the glucose reading. A hydrogel pad is used to provide contact between the sensor and the skin. The sensor contains a miniature laser that transmits pulsed light into the tissue. The light is absorbed and creates photoacoustic pulses that are detected by an ultrasound sensor and analyzed to determine the blood glucose level.

Glucon’s latest studies show that the device can identify signals that are generated from blood vessels, eliminating the contribution from glucose in the intervening tissue and interstitial fluid, and also avoiding the effects of edema on the measurement. As a result, the system can accurately monitor rapid changes in glucose, allowing prediction of short-term glucose concentration.

An initial application now under development is glucose monitoring of critically ill patients in hospitals implementing tight glucose control protocols. In that setting, the Aprise can potentially eliminate the five to six minutes required to take a fingerstick glucose measurement at the bedside, saving significant nursing time, and may also have advantages over existing continuous monitoring devices that measure glucose in interstitial fluid because of its immediate response to glucose changes, as well as its ability to monitor for extended periods, vs. a three-day limit for existing continuous monitors. The Aprise provides an updated glucose value every three seconds. An initial 30-patient study using the Glucon device showed a mean absolute relative deviation of 19% compared to a reference. A target date for commercial introduction has not yet been set.

The Medtronic Minimed (Northridge, California) unit of Medtronic (Minneapolis) exhibited its CGMS System Gold continuous glucose monitoring system, which now offers an interface between the sensor and the patient’s insulin pump, creating a semi-closed loop system. The patient remains in control of the pump. There are about 8 million diabetics in Germany now, but only about 300 physicians are using the CGMS system in diabetes management. The monitor is priced at EUR 3,100 and sensors are priced at EUR 55. A new version of the product, the Guardian RT, is scheduled for launch in 2006 that will display glucose readings every five minutes and sound alarms. However, a completely closed loop system is still in an early stage of development.

New products for professional use in POC diabetes testing also were introduced at the MEDICA exhibition. Horiba Ltd. (Kyoto, Japan) introduced the Antsense III, a transportable glucose analyzer for professional use, which shows a high degree of correlation with laboratory measurements and can be used to provide precise (3% CV) readings at the bedside using 5 microliters of whole blood. Boditech Med (Kangwondo, South Korea) exhibited the i-Chroma POC fluorometer with a test menu that includes hemoglobin A1c and microalbumin (used to screen diabetics for kidney disorders), as well as a high-sensitivity CRP assay for cardiovascular risk assessment. The $2,000 reader produces a test result in five to 12 minutes, and uses capillary whole blood samples. Test cartridges cost $2 each. The system menu also includes POC tests for cancer screening (PSA and AFP for prostate and liver cancer respectively). The i-CHROMA is available in Europe, and Boditech is applying for FDA clearance to market the product in the U.S.

DiaSys Diagnostic Systems (Holzheim, Germany) is developing the InnovaStar, a compact analyzer with assays for glucose, HbA1c and hemoglobin that will be launched in Europe in the second half of 2006. The system promises to be cost-competitive, with a target price for a hemoglobin A1c assay of around EUR 3.

Advances in diabetes treatment also were described at the MEDICA meeting. Pharmpur (Augsburg, Germany) exhibited Curavent, a new medium used for preservation of islet cells to be used in islet cell transplantation procedures. The product has the CE mark and is available in Europe, but has not yet received FDA clearance. Curavent is a biocompatible perfluorocarbon fluid that can be used to maintain islet cells after they are isolated from a donor pancreas until they are ready to be transplanted. Cost is EUR 600 for 250 ml.

Pharmpur also manufactures a device used to transport a donor pancreas. Islet cell transplants for treating insulin-dependent diabetes are becoming more widely used worldwide. In the U.S. and Canada, for example, there are now 19 islet cell transplant centers registered in the Collaborative Islet Transplantation Registry, which is maintained by the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health (Bethesda, Maryland). A total of 266 islet cell infusions had been performed in 138 patients as indicated by the registry data as of year-end 2004.

The number of procedures is not growing, however, in spite of the improved success rates resulting from use of new isolation procedures and methods to minimize rejection of the implanted cells. In part, the lack of widespread adoption is due to a shortage of pancreas donors, as well as the complexity of the transplant procedure and the need for ongoing drug treatment to prevent rejection. Improved transplant technologies, such as Curavent, could help increase the use of islet cell transplantation in the treatment of insulin-dependent diabetes.

Portable patient monitoring, diagnostics

A new product that combines POC testing with portable ultrasound imaging was recently released in Europe by Mediwatch (Warwickshire, UK). The company’s One Stop Prostate Assessment System consists of the Bioscan analyzer that performs PSA testing at the point of care and is wirelessly connected to the Multiscan 8/15 portable ultrasound system as well as the Portaflow urine flow/bladder volume analyzer. The system provides an integrated analysis of urological status, including guidance of needle biopsy procedures to check for prostate cancer in patients with suspect PSA readings. The PSAwatch PSA test is performed in 10 minutes at a cost of EUR 6, and requires a 35 microliter fingerstick blood sample. The Multiscan ultrasound analyzer, which provides high-resolution images of the prostate at 7.5 MHz and is more compact than competing portable ultrasound systems, is priced at EUR 15,000. The One Stop system is undergoing review by the FDA, and once cleared for marketing will be introduced in the U.S. by Mediwatch’s partner, Medtronic.

Advances in portable patient monitoring were another area highlighted at the MEDICA exhibition. Oxford BioSignals (Oxford, UK) introduced the BioSign monitor, which uses the company’s proprietary signal processing technology to analyze data from standard vital signs monitors such as the Intellivue from Philips Medical Systems (Best, the Netherlands) and compute a Patient Status Index (the BioSign Index). The index is a single number that indicates overall patient status, simplifying the task of monitoring patient status in the hospital, and in particular reducing the number of alarms as compared to existing monitors. The BioSign index is based on an analysis of more than five years worth of data collected on hospitalized patients, and is designed to identify clinically important trends in vital signs. Based on experience in clinical studies that have used the index, an alarm is generated only once over a one- to two-day interval, whereas conventional monitoring systems may generate up to 60 alarms in a single day, most of which are not clinically relevant.

The BioSign monitor was launched at the MEDICA exhibition, with a price ranging from $5,000 to $7,000 depending on options. A trial is under way at Clarian Hospital (Indianapolis) to study the use of the system to identify post-operative and general ward patients with deteriorating status who require a rapid emergency response. Oxford BioSignals is in the process of obtaining FDA marketing clearance for the BioSign monitor.

Remote monitoring of patients outside of the hospital setting represents an expanding segment of the medical device market in Europe. Aerotel Medical Systems (Holon, Israel), one of the leading suppliers of telemonitoring devices in Europe, introduced a new wireless 12-lead ECG analyzer that can be used in the home to monitor heart conditions remotely. The patient uses a lead assembly to collect three ECG traces and uploads the data via a wireless interface to a cellular telephone. The data is then transmitted to a server that allows the physician or monitoring service to assess patient condition from a remote computer. The company also markets optional devices for monitoring of blood pressure and body weight that can be used with the wireless system.

Telcomed Advanced Industries (Dublin, Ireland), a Medic4All Group company, introduced five new telemedicine products in November 2005, including the MiniClinic Wireless Event Recorder Wrist Unit, three new telemedicine software products, and the MedicGate Data unit, a dedicated device for wireless collection of data from home monitoring devices and transmission to a center server via standard telephone lines.

Vitaphone (Mannheim, Germany), which has been a player in the remote monitoring sector in Europe since 1999, introduced a new wearable loop recorder for ECG monitoring with an adjustable loop time that interfaces with its cell phone-based remote monitoring system. Vitaphone’s primary product is the Vitaphone 2300, a combination ECG monitor and cellular phone in a compact package similar in size to a standard cell phone that can be used for spot recording of ECG and transmission of the data to a monitoring center.

About 50,000 patients are now being monitored with Vitaphone devices in Europe. In Germany alone, 1.3 million people have cardiac insufficiency, and there are more than 350,000 heart attacks annually, half of which are fatal. In addition, there are about 80,000 cases of sudden cardiac death annually, with tachyarrhythmia the most frequent cause. The Vitaphone monitor is intended as a tool to identify those individuals at risk for such events, allowing intervention to prevent occurrence.

Another segment of the patient monitoring and diagnostics market that is experiencing attractive growth is the diagnosis of sleep disorders, including sleep apnea, as well as monitoring of infants to prevent sudden infant death syndrome (SIDS). The market for products used in the diagnosis of obstructive sleep apnea (OSA) has considerable growth potential according to suppliers of sleep diagnostic products, since in the U.S. alone about 20 million people are afflicted with OSA but only about 5% have been diagnosed.

One of the leading suppliers of sleep disordered breathing products, ResMed (North Ryde, Australia), has achieved 29% compound annual growth in revenues over the past four fiscal years. The global market for sleep-disordered breathing products, including products used for diagnosis, monitoring and therapy, is estimated at over $800 million in 2004, based on data from suppliers, and is projected to approach $1.7 billion by 2009, as shown in Table 3. ResMed introduced a new CPAP device at the MEDICA exhibition, the S8 System, for use in the treatment of OSA. The S8, a compact device that can be held in one hand, can interface with the HumidAire 3i humidifier to create a highly compact positive airway pressure/humidifier system.

Other suppliers of sleep apnea diagnosis and therapy products exhibiting at MEDICA include S.L.P. Ltd. (Lake Charles, Illinois), with the Smart Sensor family of sensors for at-home sleep testing; Weinmann (Hamburg, Germany), exhibiting the new Artisan software for polysomnography analysis; SOMNOmedics (Kist, Germany) with the SOMNOscreen handheld polysomnography system; Medcare Flaga (Reykjavik, Iceland), with the Embletta family of sleep diagnosis and monitoring products; and Fukuda Denshi (Tokyo), which will soon introduce the S.A.S. Portable Sleep Polygraphy System.

The S.A.S. is a wearable device that will offer improved patient comfort and allow sleep studies to be performed in a wide range of sites. The SOMNOscreen device is a portable 28-channel recorder that can transmit sleep data wirelessly to a PC for physician analysis. Medcare’s Embletta pds is a pocket-sized digital sleep recorder used for ambulatory sleep studies.

Getemed (Teltow, Germany) also is a participant in the home monitoring market with its VitaGuard monitor for SIDS telemonitoring. The VitaGuard uses wireless technology to allow vital signs data to be transmitted over a range of up to 10 meters. Parameters monitored include heart rate, respiration, oxygen saturation and ECG. Data from the monitor can be interfaced directly to the Internet to allow remote analysis from virtually any location.

Diagnostic imaging and image-guided therapy

New developments in diagnostic imaging are allowing an increasing proportion of diagnostic procedures to be performed in a non-invasive or minimally invasive manner, further diminishing the use of exploratory surgery and invasive biopsy. In addition, advances in imaging technology are driving progress in image-guided therapy, which is a rapidly expanding field impacting a wide range of clinical disciplines, encompassing areas such as endoscopy, interventional MRI, microsurgery, and minimally invasive surgery.

A number of companies have recently introduced new imaging technologies for use in endoscopic exams. For example, Fujinon (Saitama, Japan) has introduced the Series 500 Super CCD series of video endoscopes, including an option called Fuji Intelligent Chromo Endoscopy, or FICE. The FICE option uses a technique called Spectral Estimation Technology to process the video data from the CCD detector array in the videoscope, generating an image that consists of contributions from only a single wavelength of reflected light. The technique provides a significant improvement in discrimination. For example, when examining tissues in the esophagus, FICE allows blood vessel orientation to be visualized, whereas in the full-spectrum image the same region is virtually featureless. Furthermore, because FICE uses electronic processing to isolate a wavelength of interest, it is possible to switch between the ordinary full-spectrum image and the FICE image in less than a second. Other approaches employing optical filters to isolate a wavelength band do not allow such rapid switching between modes.

FICE has been shown to allow more precise determination of the boundaries of cancerous lesions than conventional endoscopic imaging, an important feature in guiding tumor excision. Different features, such as underlying blood vessel orientation versus characteristic surface features of tissue, are optimally viewed at different wavelengths, and FICE allows rapid switching between different wavelengths to select the optimum setting. Other potential applications of FICE are being explored.

Pentax (Tokyo), another leading supplier of endoscopy products, is developing Confocal Endomicroscopy for a variety of applications. Confocal Endomicroscopy is a patented fluorescence-aided, single fiber optical biopsy technique that enables in vivo microscopic subsurface examination of cellular structure. It promises to allow real-time endoscopic diagnosis that is equivalent to histologic diagnosis. Pentax has been conducting clinical trials of the technology for about a year, and plans market introduction this spring of 2006. Among the applications under development are screening for gastric cancer and pre-cancerous lesions in at-risk populations, as well as rapid diagnosis of H. pylori infection. Surveillance for Barrett’s esophagus is another potential application under study.

Another approach to optical biopsy was described by SIRA (Kent, UK) at the MEDICA conference. SIRA (Scientific Instrument Research Associations) has developed an optical coherence tomography (OCT) scanning probe that can be used to examine sub-surface tissue structure in vivo. The company is planning to commercialize the technology for biomedical applications via a spinout to be called Michelson Diagnostics. The technology, originally developed at the University of Vienna, involves the use of wavelength scanning and Fast Fourier Transform (FFT) processing to allow features as small as 10 microns to be discriminated, and also can penetrate beneath the tissue surface to a depth of 2 mm. OCT is analogous to ultrasound, but with significantly higher resolution.

Applications under development include guidance of tumor resection via intra-operative imaging with resolution approaching that of histology without tissue removal. The probe may prove particularly valuable in lung cancer surgery. Another application is in cervical cancer diagnosis, where the OCT probe may replace diagnostic punch biopsies in the assessment of cervical lesions. The company is seeking investment from a commercialization partner to bring the technology to market, and estimates that about three years will be required to ready the product for launch.

Olympus (Tokyo) introduced a new capsule endoscopy system at MEDICA, the EndoCapsule. Capsule endoscopy was first developed by Given Imaging (Yokneam, Israel), and employs a pill-sized, biocompatible camera that is swallowed by the patient. The camera transits the gastrointestinal tract and acquires a series of images that are transmitted wirelessly outside the body and stored. A gastroenterologist can then view the reconstructed images to examine the bowel without the need to insert an endoscope. The technique is particularly valuable for examination of the small bowel, where conventional flexible endoscopy is challenging and entails risk of perforation.

The EndoCapsule, now available in Europe, is a single-use device priced at EUR 600 per capsule that consists of white-light LEDs, a lens, a CCD chip and an RF transmitter. About eight hours are required for the capsule to transit the GI tract. The device features automatic control of the LED light sources to avoid over- or underexposure of the image. While resolution is not as high as contemporary videoendoscopes supplied by Olympus, it is adequate for small bowel exams.

Another capsule endoscopy device was exhibited by Jinshan Science & Technology (Chongqing, China) that also is targeted at applications in small bowel examination.The OMOM Capsule Endoscopy System offers an image resolution of 0.1 mm, and uses a capsule measuring 25.4 mm in length and 11 mm in diameter. A clinical trial of the device found that it could successfully detect gastrointestinal disease in 80% of cases, vs. a 35% success rate for contrast imaging.

Magforce Nanotechnologies (Berlin) showed a new technology, Magforce Nanotherapy, for use in image-guided cancer therapy that is based on tumor-targeted magnetic nanoparticles. The technology is based on 18 years of research conducted at Charite University (also Berlin). The Magforce nanoparticles consist of an iron oxide core surrounded by a silane coating. The coating is modified by attachment of tumor-specific compounds that promote selective adhesion to particular tumor types, such as glioblastoma and prostate tumors.

Magforce has developed in vitro culture methods to allow isolation of a variety of tumor types of interest, and used the cultured cells to screen for compounds that adhere to a specific tumor type. The particles are injected into a tumor and preferentially migrate into the tumor tissue. The company’s MHF 300F magnetic field therapy system is used to magnetically excite the nanoparticles, which respond by generating heat in the tissue. The degree of temperature elevation can be precisely controlled, allowing a variety of different effects to be produced. At high temperatures above 70 C, tumor ablation occurs. At lower temperatures, typically below 45 C, heat can be used to potentiate the activity of chemotherapeutic drugs by eliminating resistance mechanisms such as proteins that pump drugs out of target cells. Heat can also be used to enhance the effects of radiation therapy at a specific tumor site.

Chemotherapeutic drugs can also be coupled to the particles to allow targeting of the drug to the tumor, and then released and activated upon exposure to the magnetic field, concentrating the drug’s effect at the tumor site and minimizing systemic exposure of the patient to toxic compounds. That approach has a potential side benefit of providing patent protection for older drugs that have gone off patent, since the coupled drug represents a new agent, according to Magforce. The particles remain in the tissue for at least six months, allowing re-treatment if using modalities such as radiation therapy, for example. Magforce is searching for strategic partners that can help commercialize the technology in the U.S. and Europe.

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