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Articles from 1999 In March


Surface modification



Surface modification

Cold gas plasma technology

Cold gas plasma surface treatment, which is conducted in a vacuum, allows designers to chemically change the surface of a plastic to suit a particular need. Applications include surface cleaning or promoting adhesion. The 600-series plasma system features an ultraclean quartz chamber with no metal parts inside, preventing parts from being exposed to the particulates associated with metal chambers. Furthermore, inductive coupling ensures multidirectional cleaning or surface modification. Anatech Ltd., 6621F Electronic Dr., Springfield, VA 22151-4303.


Surface modification system

A surface modification system can be used for a variety of surface treatments. Its chamber size is designed to meet customer specifications, and, in order to ensure uniform surface exposure, the system offers a patented gas-reversal feature. The system performs ultracleaning of medical devices such as angioplasty balloons, catheters, filter materials, syringe hubs, and intraocular lenses. Gas plasma technology is also used to increase bond strength, lubricity, wettability, and other characteristics. Operating costs are low and productivity is high since minimal power is required for plasma processing. For monitoring of temperatures and process values, specialized software ensures process uniformity. Advanced Plasma Systems Inc., 12000 28th St. N., St. Petersburg, FL 33716.


Custom electrical-discharge equipment

Custom equipment is available for the surface modification of polymers such as polypropylene, polyethylene, polyester, polystyrene, Teflon, polyurethane, and silicone. The surface modification process uses electrical discharges or coronas to increase the bonding sites of the polymer surface for increased adhesion of inks, paints, coatings, and adhesives. The process is conducted at atmospheric pressure and is easily integrated into production lines. Specialty shaped electrodes can treat many different 3-D surfaces. Also included is a high-powered multifunctional generator. Tantec Inc., 630 Estes Ave., Schaumburg, IL 60193.


Automated gas plasma system

A microwave gas plasma system is designed for high-volume surface modification and ultrapure cleaning. Typical applications of the Model V170-G include polymer surface modification for increased wettability or hydrophobicity, plasma thin-film coatings (barrier, lubricious, or primer), and ultrapure cleaning of metals and ceramics. The unit features microwave/dual frequency for high throughput rates, a large electrode-free chamber, and microprocessor control with stored-recipe capability. A fully integrated automated handling system can be customized to minimize operator involvement and accommodate specific production environments. Plasmatech Inc., 1895 Airport Exchange Blvd., Ste. 190, Erlanger, KY 41018.


Surface modification for improving biocompatibility

Although products composed of materials such as plastics, polymers, and resins are designed to meet specific requirements, interactions within the body or in the laboratory can limit their performance. In cases where such materials fail to provide the desired level of biocompatibility, plasma surface modification can enable engineers to control or enhance thrombogenic biocompatibility, protein attachment, platelet retention, barrier layers, and cell attachment. A manufacturer offers the 7100-model plasma system for such applications. Metroline Industries, 251 Corporate Terr., Corona, CA 91719.


Plasma system with tumbler basket

A plasma system with an integrated tumbler basket has been added to a manufacturer's line of surface modification equipment. The tumbler feature is suitable for the plasma treatment of large volumes of small parts. Two models are available, one with a 1-cu-ft basket and the other with a 5-cu-ft one. The feature provides users with alternatives for plasma treatment. 4th State Inc., 1260 Elmer St., Belmont, CA 94002.


Corona treating systems

Corona treatment increases the wettability of polymer surfaces, allowing adhesion for printing, coating, and bonding applications. In addition, the MultiDyne 2 corona treating system can process petri dishes, test panels, and other disposable laboratory products for enhanced surface characteristics. The device's generator is connected to a single-phase power line (200–250 V, 50–60 Hz) and it can be used as a stand-alone unit or be interfaced to a manufacturing line. Softal 3DT LLC, N114 W18850 Clinton Dr., Germantown, WI 53022.


Unbalanced magnetron sputtering

A coating system incoporating unbalanced magnetrons in a patented "closed field" arrangement offers flexibility, reliability, control, and ease of use. Process parameter details for virtually any coating can be included in the technology transfer package that accompanies all systems. According to the manufacturer, coatings are deposited with the highest level of ion current yet available—but at low-bias voltage to ensure dense structures with low internal stresses and good adhesion. Deposition is possible at low temperatures while retaining these properties. Total control of reactive processes is provided by an optical emission system. Multi-Arc Inc., 200 Roundhill Rd., Rockaway, NJ 07866


Plasma treatment system

The PT-2000 plasma treatment system increases the adhesion characteristics of almost any nonconductive material, including plastics, silicone, rubber, resins, and fluoropolymers. The PT-2000 is suited for applications that require improvements in the gluing, potting, marking, painting, or coating of a nonconductive material. Typical applications include the treatment of connector shells, connector inserts, and PC boards. Tri-Star Technologies, 2201 Rosecrans Ave., El Segundo, CA 90245.


Plasma systems

Custom vacuum chambers and electrode configurations for any part size are available for a company's plasma systems. High- and low-frequency RF generators, computer and manual control systems, and process temperature controls are all incorporated. Also available are multiple gas flows, up to three gas-flow controllers, and an automated vacuum-chamber door. Applications include sterilizing, increasing adhesion, promoting bonding, and depositing nonstick, slippery coatings. Plasma Etch, 3522 Arrowhead Dr., Carson City, NV 89706.

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Packaging Costs Reduced with Formable Bottom Web



Medical Packaging

Packaging Costs Reduced with Formable Bottom Web

Designed for use with uncoated Tyvek or paper top webs

BY USING A FLEXFORM P formable bottom web, device manufacturers can switch to uncoated Tyvek or uncoated paper top webs to save on packaging costs while at the same time producing smooth, peelable seals. Rollprint Packaging Products (Addison, IL) coextrudes FlexForm P with its new polymeric peelable sealant to minimize bottom web material and eliminate the expense associated with coating the top web.

The FlexForm P formable bottom web produces smooth, peelable seals.

When the seal between the bottom and top webs is broken, the film turns uniformly white. Users accustomed to seeing white seal transfers with conventional coated Tyvek will find packages made with FlexForm P virtually identical to them.

FlexForm P is produced with a Surlyn ionomer core, a low-EVA copolymer on the outside layer, and the polymeric peelable sealant material on the inside. It is available in thicknesses ranging from 4 to 10 mil, provides good durability, and is suitable for EtO sterilization. Compared to packages using Tyvek or paper, package breathability is improved and EtO cycle times and sterilization creep are reduced, according to Rollprint. FlexForm P is compatible with most forming equipment and does not require modifying the machinery.

For more information, contact Rollprint Packaging Products at 630/628-1700.

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Electronic Components

Ultraminiature Resonators Deliver Wide Frequency Range

Suitable for portable devices

GOOD RESONANT CHARACTERISTICS and high resistance to shock and vibration make the SSR series of ultraminiature ceramic-chip resonators suitable for use in portable medical equipment. Recently introduced by AVX Corp. (Myrtle Beach, SC), the units provide electronics design engineers with a high-performance timing device in a tiny, surface-mount package.

Measuring only 3.2 x 2.1 x 1.5 mm, the SSR-series chip resonators are a high-performance timing device in a tiny, surface-mount package.

According to AVX Corp., the SSR series are the smallest chip resonators available, at 3.2 x 2.1 x 1.5 mm. They incorporate built-in load capacitors that simplify circuit design and reduce assembly costs. Operating frequency range is from 16 to 60 MHz (±0.5%), and several standard frequencies are also available. Resonant impedance is a maximum of 100 , with a temperature stability of ±0.3% over an operating temperature range of -20° to 80°C.

For more information, contact AVX Corp. at 843/946-0414.

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Surface Modification

Surface-Texturing Process Promotes Bond Integrity

For bonding metallic and nonmetallic surfaces

BOND INTEGRITY between metallic and nonmetallic surfaces, such as that between an implant and bone, can be improved with the Chemtex surface-texturing process. Provided by Cycam Inc. (Houston, PA), the service allows engineers to design the height, depth, and location of the surface texture, and to avoid the problems associated with plasma sprayed, sintered, or bonded materials.

The Chemtex process produces a random, irregular pattern on surfaces, promoting bone growth and providing a strong attachment for it.

A repetitive masking and chemical or electrochemical milling process forms a random, irregular pattern on the surface. This process is repeated several times, as necessitated by the nature of the features required in the surface. Time, temperature, and the number of repetitions used in the etching process control the surface characteristics. Material is removed from the implant surface without stress on the adjoining material, and the process provides fully dimensional fillet radii at the base of the surface features.

The textured surface is adapted to allow the growth of bone materials and to provide a strong anchor for that bone material. The unitary nature of the substrate and surface features provides a strong anchoring surface that is resistant to cracking or breaking.

For more information, contact Cycam Inc. at 724/745-7272.

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A Pain-Free Alternative for Diabetics



A Pain-Free Alternative for Diabetics

User-Centered Design Was the Key to Bayer's Award-Winning Lancet

By Sally Lane, Senior Editor

For diabetics, monitoring blood glucose levels is a daily fact of life. The tests allow them to quickly assess their blood chemistry in order to circumvent life-threatening elevations or declines in blood sugar. Proper monitoring can mean up to nine tests a day, each one requiring a painful needle stick in the finger.

Seeing the need for a less painful, easy-to-use testing device, Bayer Corp.'s Diagnostics Business Group (Elkhart, IN) approached Metaphase Design Group (St. Louis) to create a state-of-the-art lancet. The result was the Bayer Microlet Automatic Lancing Device, which has been a commercial success for Bayer and resulted in a prestigious design award for Metaphase.

Getting to "Yes"

For Metaphase, one of the first steps in the design process was to conduct extensive one-on-one interviews with diabetic patients of various ages and levels of disease to "learn how they live with their disease," says Bryce Rutter, CEO at Metaphase. "The discovery phase included trying to understand what their wish list was, the problems they currently experienced with existing devices, and the ergonomic constraints they would pose on a product like this," he says.

One problem identified with the existing devices is that they are difficult to operate. Traditional pen-shaped lancets require the user to grasp the device with three fingers and stand it up vertically so the only thing touching their hand is the tip of the pen, Rutter explains. "When you think about trying to hold a pen-shaped device to stick your finger, it's probably the worst design going," he says. "It's also difficult to see where you're going to prick yourself." To complicate matters, many diabetics have vision or motor control problems, making such devices even more difficult to operate.

Metaphase also asked the research subjects how often and where they conducted their blood tests, and asked them to bring their current diabetic supplies to the interview site, transporting them in the way they typically would. "We videotaped and documented how much junk they had to carry and the ways they had personalized it," Rutter says. This research revealed that convenience was one of the users' main concerns. "The vast majority said, 'Why does all this stuff have to look like medical equipment, and why is it so large?' " The group members asked for a product they could conceal in their hand when using, and for a device they could carry in their pocket.

To conduct a blood test with the Microlet the user simply inserts a lancet until it clicks into place, positions the device against a finger, and presses the release button.



"We showed them a set of first-tier designs and asked them a battery of questions related to their perception of various aspects of product performance. We then showed them a set of second-tier designs, and, lo and behold, everyone pointed to the same design!" It featured a small, flat device that fit in the palm of the hand and was easy to manipulate.

"We tried to design the Microlet based on the worst-case scenario, so that it would allow someone to operate it using gross motor control rather than precision motor control," Rutter says. To make the device easy to operate, Metaphase textured the "grip" to guide the user's hand. They also colored the grip and the release button so people with vision problems could see them better. Another design innovation was to curve the lancet port so users would have a better view of the lancet contact point when conducting a blood test.

The Production Process

Metaphase approached Bayer's engineering team with what they thought was a foolproof design, but the Bayer engineers were convinced the design couldn't be mechanically executed. "They said you can't take a linear mechanism and cut it in one third and make it happen," Rutter says. Despite the challenges it presented, Joe Ruggiero, Bayer's director of engineering for instrument systems, was determined to create the new product, Rutter says.

Given the green light, Metaphase created scale models out of high-density foam. "We identified a short list of designs we felt were the most promising, then developed photorealistic illustrations on a computer," Rutter says. After developing two-dimensional foam models, Metaphase researchers met again with the diabetic subjects to obtain feedback on the designs' potential usability and ergonomics. The winning design from this phase was then documented with CAD drawings for the Bayer engineers, who in turn executed the mechanical design of the Microlet. Once this stage was completed, prototypes were constructed and tested internally.

Not only did Bayer engineers figure out how to execute the design, but "they did something really cool," Rutter says. They created a mechanism for the Microlet that would deliver a more precise, less painful, finger prick. The traditional pen-shaped devices are designed in such a way that when the needle hits, it bounces back and pricks the finger a few more times around the initial puncture site, Rutter says. "According to research, one of the major contributors to pain is the second, third, and fourth strikes of the lancet," he says. The Microlet eliminates this problem by sticking the user only once. In one study conducted by Bayer, 94% of the patients who tested the Microlet said they found it less painful than the product they were currently using.

In addition to usability issues, aesthetics were also a concern in designing the Microlet, particularly when it came to deciding where to place the product's parting lines. "In any small handheld product, you must place the parting lines to accentuate the form and quality of the product and place them in a way that they cannot be detected by the hand," Rutter says. In terms of materials, it was pretty much a "no brainer," Rutter notes. "Bayer chose materials typically used in medical devices—ones that won't stain and that are easy to clean and color. They also needed to choose materials that could take the shock and impact typical in the use of a lancet."

The end product consists of a durable ABS plastic shell and a stainless-steel needle. After looking at several manufacturing methods, Bayer chose an injection molding process because of its ability to produce high volumes of precision parts.

Everybody Wins

Bayer's Microlet, introduced to the marketplace in 1997, has been a "stellar success," Rutter says. The device also reaped a 1998 Good Design Award for Metaphase. The microlet is being included in the permanent collection of The Chicago Athenaeum, Museum of Architecture and Design, the sponsor of the competition.

Rutter cites user-centered design as the key to the product's success. "Robert Williams, Bayer's manager of product planning and business development, believed that Bayer shouldn't develop the product internally because they're not diabetics. I know it sounds logical, but the vast majority of products are developed by manufacturers with no more than traditional market research. The outcome is that Bayer has made life better for diabetics and, as a result, made life better for themselves, in terms of sales."

MPMN is seeking success stories like this. If your company has one to share, please contact managing editor Karim Marouf at 11444 W. Olympic, Ste. 900, Los Angeles, CA 90064-1549; 310/445-4200 or e-mail karim.marouf@cancom.com.

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Pressure-Sensitive Adhesives



Pressure-Sensitive Adhesives


PSA contract manufacturing

Rotary and reciprocating die-cutting, laminating, slitting, level winding, and custom sterilizable packaging are offered by a company catering to the medical device industry. It maintains multiple cleanrooms with pressure, particulate, and temperature/humidity monitoring controls, as well as adjacent white rooms for packaging. The company follows GMPs and is both drug and device registered with FDA. It is experienced in sourcing PSA films, foils, and double- and single-coated foams, as well as conductive adhesives, hydrogels, and hydrocolloids. Technical development functions include prototyping, short clinical evaluation runs, design of experiments, process validation, and first article capabilities. Tapemark, 1685 Marthaler Ln., West St. Paul, MN 55118-3537.


Medical tapes

A line of medical tapes and adhesives can be used on sensitive skin, adhere to difficult substrates, provide moisture resistance, withstand the stresses of sterilization, and deliver a high moisture vapor transmission rate. The manufacturer also develops short- and long-term dermal adhesive systems with low- or no-residue features. Tyco Adhesives, 15 Hampshire St., Mansfield, MA 02048.


Breathable wound dressing

Breathable medical-grade adhesive film is designed for use as a wound dressing and other direct skin applications. It consists of a clear urethane film coated with hypoallergenic acrylic adhesive. The adhesive is pattern coated onto the urethane film, resulting in increased breathability and a high moisture vapor transmission rate (MVTR). High-MVTR films allow wounds to heal quickly because the wounds are exposed to air yet protected from contaminants. The dressing is highly conformable to irregular surfaces and can be easily removed from the skin. Because it is clear, the film lets medical personnel monitor the healing progress. Scapa Tapes North America, 111 Great Pond Dr., Windsor, CT 06095.


Custom PSA conversions

A company has expanded its capabilities to offer critical processing of adhesive materials to accuracies in the range of ±0.002 in. In conjunction with the ISO 9001–certified company's coating of custom adhesive materials, this converting capability produces diagnostic kit components, strip assemblies, island placements of dissimilar multiply laminated substrates for custom fabrications, and precisely imaged identification and dosage measurement calibrations. Topflight Corp., P.O. Box 2847, York, PA 17405-2847.


Die-cutting and slitting

A company offers custom die-cutting and slitting of PSA components. Services include four-color printing and laminating adhesives to nonmetallic materials such as vinyl or film. A Class 1000 cleanroom and a low-humidity dry room are used for converting sensitive medical parts. Clients provide the chemically treated materials that are then slit in the dry room and laminated with an adhesive to an assortment of backing materials. G & L Precision Die Cutting Inc., 1766 Junction Ave., San Jose, CA 95112-1018.


Adhesive-backed products

A contract manufacturer of adhesive-backed medical products and components specializes in custom rotary die-cutting, laminating, printing, island placement, prototyping, and flexible packaging. Materials regularly converted include adhesive-backed films, foils, wovens, nonwovens, foams, and hydrogels. Applications include wound dressings, hydrogel dressings, tube holders, suture strips, cosmetic disposables, and many other devices. In addition, this ISO 9002–certified company offers a turnkey package complete with sterilization. Heat- or cold-seal single-use pouches are available constructed of papers, films, Tyvek, and foils. TTL Medical, 10537 Lexington Dr., Knoxville, TN 37932-3212.


PSA with enhanced drug compatibility

Featuring enhanced drug compatibility, an adhesive has been designed for transdermal applications. Duro-Tak 87-4098 provides good cohesion because of its high internal strength. Shear tests show a holding power of approximately 4 psi for 10 hours at 72°F. The acrylic copolymer product is not cross-linked and is free of functional groups, making polymer-drug interaction minimal and allowing the adhesive to be used with highly reactive drugs. The solvent system is 100% ethyl acetate, which greatly simplifies the analysis performed by the end-user. National Starch & Chemical Co., 114 Mayfield Ave., Edison, NJ 08837.


Converting and fabrication

An FDA-registered and ISO 9002–certified company offers full-service converting and fabrication of pressure-sensitive materials for use in diagnostic test strips and transdermal and skin patches. The company also offers narrow-width slitting of single and multilayer pressure-sensitive material. A variety of soft, semirigid, and thin-rigid materials are laminated with medical, electrical, or industrial-grade PSAs to meet various performance levels. Pacific Die Cut Industries, 3399 Arden Rd., Hayward, CA 94545.


Converting services

An FDA-registered and ISO 9002–certified converter of pressure-sensitive medical components and diagnostic devices offers custom die-cutting, multilayer lamination, spooling, and printing. Butterfly liners, thin films, nonwovens, and hydrogels are routinely processed. Also offered are in-house island placement, zone adhesive, and cleanroom capabilities. Traceability is ensured through in-house QC and SPC. M&C Specialties Co., 90 James Way, Southampton, PA 18966.


PSAs for various applications

Two pressure-sensitive adhesives are used in such applications as bonding electrodes to the skin. A dispersion is applied to the skin or to the device, and when it evaporates it leaves behind a tacky silicone layer that can be adhered to another object through application of pressure. The PSA-9673-10 adhesive has an ethyl acetate carrier that is an industry standard, and PSA-7672-10 is unique in that the carrier is a silicone. This silicone—hexamethyldisiloxane—is relatively odorless and is listed by the EPA as a nonvolatile organic compound. NuSil Technology, 1050 Cindy Ln., Carpinteria, CA 93013.


Conformable incise tape

A conformable incise tape conforms to body contours and stretches to allow limb manipulation while it securely adheres to the wound edge. The durable, breathable tape transmits ample moisture vapor to minimize skin damage over long procedures, but it isn't permeable to liquids and thereby preserves the integrity of the sterile field and prevents bacteria from entering the wound. Being resilient and durable, the film also helps prevent liquid strike-through during surgical procedures. 3M Health Care, 3M Center, Bldg. 275-4E-01, P.O. Box 33275, St. Paul, MN 55133-3275.


PSAs for diagnostic testing products

Medical-grade PSAs are available in card form for customers who have small or semiautomated production runs of diagnostic testing products. One product, ARcare 8565, is a firm tape product to which membranes can be laminated. It has a 10-mil white PET carrier with a 2-mil clear liner. This white film provides enhanced visual readability. Another adhesive, ARcare 7815, is applied to the top of the total construction. It uses a thin, flexible, and clear 2-mil PET carrier that helps facilitate the flow of the patient sample to the membrane, while at the same time protecting the indication area from exposure to unwanted sample. Adhesives Research Inc., P.O. Box 100, Glen Rock, PA 17327.


Custom PSAs

A manufacturer of custom pressure-sensitive adhesive components offers flexographic printing, precision rotary or flat-bed die-cutting, and multilayer lamination. The company has manufactured components for pulse oximetry, wound care, incontinence management, transdermal drug delivery, drug infusion therapy, gas monitoring, laparoscopy, muscle/nerve stimulation, diagnostic testing, iontophoresis, and sleep apnea monitoring. It also fulfills specialty packaging application needs, including tamperproof seals, antifog package windows, and custom-patterned adhesive lidding. Acutek, 540 N. Oak St., Inglewood, CA 90302.

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Products Featured on the cover of MPMN

Products Featured on the cover of MPMN

Earless linear actuator provides precision in tight spaces

The slim profile of a 20-mm-diam earless linear actuator makes it suitable for medical applications requiring precise motion in a limited space, such as handheld devices. Because the actuator does not have a mounting flange, it can fit in a 20-mm-diam area. The Z-series actuator can lift up to 60 oz and is available with linear step increments of 0.001, 0.002, and 0.004 in. travel per step. The motor is offered with bipolar and unipolar coil windings and can be mounted with clamps, threaded front sleeves, or snap-in mounting. Haydon Switch & Instrument Inc., 1500 Meriden Rd., Waterbury, CT 06705.




Polyurethane film welding system creates strong, invisible seals

A proprietary Class 10,000 cleanroom thin-film welding system can be used to manufacture nearly any thin polyurethane film product and create a seal that is nearly invisible and is as strong as the material itself. The system produces weld strengths of up to 2500 psi for films ranging from 1 to 10 mil thickness, and can be used to create products up to 18 in. wide by 24 in. long. Applications include organ bags, oversized pressure cuffs, medical instrument and scope covers, protective barrier sleeves, and specimen and tissue bags. The company can provide components or fully fabricated and assembled products. Polyzen Inc., 115 Woodwinds Industrial Court, Cary, NC 27511-1487.




Wires facilitate arterial, venous, and subcutaneous access

A company offers access, interventional, and specialty guidewires and components for cardiology, radiology, critical-care, minimally invasive surgery, urology, and gastroenterology applications. Access guidewires for percutaneous catheter placement are safe, kink resistant, and easy to use. Custom variations can be engineered to meet specific applications. Interventional guidewires are available with fixed or movable cores, PTFE coating, and heavy-duty construction. The company also offers components such as open coils, ground core wires, coated wires, dispensers, and coil clips. TFX Medical, Tall Pines Park, Jaffrey, NH 03452.



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Keeping Pace with Technology

Editor's Page

Keeping Pace with Technology

Product researcher and designer Bill Evans says that he is old enough to have learned all the traditional skills of his profession just before they became obsolete. As the founder of San Francisco–based Bridge Design, Evans has put away the pencil and drafting board and fullheartedly embraced the digital era. He considers the current digital technologies to be baby steps, however.

On his Web site http://www.stevensonsrocket.com he compares the state of digital technology to Stevenson's Rocket, an early steam locomotive. In 1829 the Rocket astounded its bystanders by reaching 29 mph. In fact, one observer was so excited that he fell in front of the Rocket and became an early victim of steam power. Just as the Rocket's viewers were impressed by its remarkable speed, we are similarly impressed by digital technology, even though it is in its infancy, Evans says.

Although the technology may be immature, designers and engineers at companies that have invested in the newest digital tools are seeing dramatic changes in how they collaborate and interact with other team members and clients. Until recently, only those fluent in CAD had the capability to view and maneuver electronic design files. Now, however, new technology offers the potential for anyone with Internet access to view a design concept. Currently, nontechnical users may face difficulties in using virtual reality markup language (VRML), one mode of viewing designs on-line. Eventually this capability will run smoothly in all Internet browsers. Digital technology "will ultimately make designing quicker and more intuitive to a broader range of people," Evans says.

With programs such as Shockwave, designers can transmit via e-mail or on secure Web site pages interactive models of complex medical device interfaces that are sophisticated enough to generate user feedback early in the design stage. With the ease and speed of sending and viewing designs on-line, developers have the opportunity to increase the amount of design iteration, ideally resulting in better products created during shortened development cycles. Whereas previously design changes took place through the medium of back-and-forth overnight mail exchanges and file compatibility was problematic, now with the right tools, modifications can be made and shared with work groups all in the space of one afternoon.

Electronic communication and technology continue to reduce the barriers to design and engineering collaboration. Project-based secure Web sites and digital technology promote collaboration among design team members in remote locations, between designers and clients, between parts designers and manufacturers, between designers and marketers, and ultimately involves feedback from more decision makers earlier in a product's development.

Some companies are postponing investing in new digital technologies, waiting until the technologies have attained a proven level of utility and applications have become easier to use. In doing so, they may find themselves in the same position as that unfortunate victim of Stevenson's Rocket. With technology's potential for shortening development cycles and exploring more design iterations, companies well versed in the newest programs will have the competitive advantage.

Amy Allen
amy.allen@cancom.com

How Now, Mad Cow?Strong Measures to Forestall a Potential Killer

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI March 1999 Column

Taking a hard look at the past, the British government enacts extraordinary policies to combat what is still a hypothetical risk.

One of the unusual and ominous characteristics of the last twenty-five years or so of medical history has been the emergence of new and devastating infectious diseases. These have spawned a series of crises ranging from the deadly but relatively circumscribed Ebola fever outbreak of the mid-1970s to the monumental and ongoing disaster of the AIDS pandemic.

The most recent episode, in 1996, involved the eruption of "mad-cow disease"—or bovine spongiform encephalopathy—among livestock in Great Britain, and the probable transmission of the infectious agent to 31 people. "Probable" because there remains little definitive knowledge about the origin of the malady, the manner in which it spreads, or the source or extent of the contagion in humans, where it is known as "new-variant Creutzfeldt-Jakob disease."

Despite these uncertainties, recent research suggests the possibility that the uniformly fatal disorder could be transmitted through transfusions of certain blood components from unknowing carriers. With no screening test available, this threat has prompted the British government to undertake the costly and unprecedented step of destroying nearly all of the plasma and white cells from the country's entire blood supply in an effort to cut the risk of future infection. The plasma—the protein-containing, fluid portion of the blood used in the manufacture of various blood products—will be replaced with plasma from the United States, where the disease has not been reported.

If all of this sounds familiar, it is because the scenario is eerily reminiscent of the situation that existed in the early years of the AIDS crisis, when the topic of debate was the safety of the U.S. blood supply. The difference is that the British seem to have learned from our mistakes, and prefer erring on the side of caution as opposed to erring on the side of a reckless disregard for the lives of thousands of potential victims.

Whether we have learned from those same mistakes is open to question. Judging by his published comments—that the British response, "based on a theoretical risk only," is thus "a bit extreme"—the chief medical officer of the American Red Cross appears particularly oblivious, given the lamentable role of the Red Cross and the rest of the U.S. blood-banking industry during the early 1980s, when mounting evidence that AIDS could be transmitted through blood was similarly termed an overreaction.

As in every significant medical emergency, the "mad-cow" phenomenon has resulted in commercial ramifications involving the device industry. Companies supplying bovine- or other animal-derived products have been forced to reevaluate the safety of their materials and institute stringent source control and validated methods for eliminating or inactivating transmissable agents. Other firms stand to benefit, especially those equipped to provide the white-cell filtration, or "leucocyte reduction." This procedure apparently enhances transfusion safety in a variety of ways, including the removal of numerous blood-borne viruses and bacteria, and is under consideration by FDA for more generalized adoption.

Determining whether the extraordinary preventive measures implemented in Britain are finally a waste of time and money—as is fervently hoped—will take a number of years, since new-variant CJD remains dormant for long periods. Viewed as a disbursement of moral capital, however, the soundness of the actions seems beyond reproach.

Jon Katz
jon.katz@cancom.com


Copyright ©1999 Medical Device & Diagnostic Industry

Reprocessing Single-Use Devices: An Undue Risk

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI March 1999 Column

FIRST PERSON

According to a trade organization official, the reuse of medical devices originally designated for single use raises serious concerns about safety, effectiveness, and equitable FDA oversight.

If you were being wheeled into surgery, would you be comfortable knowing that your surgeon would be reusing a disposable medical device during the procedure without anyone having studied whether that device was still safe and effective?

Assuming that one knew this was going to happen (and the vast majority of patients do not), I doubt many of us would approve. Nevertheless, numerous healthcare facilities are engaging in this practice without fully evaluating whether the devices they are reusing have been compromised or contaminated.

Without question, the reuse of medical devices is increasing as hospitals and other healthcare facilities look to contain costs. However, the reprocessing and subsequent reuse of medical devices intended for a single use raise a variety of concerns for manufacturers.

In ensuring the safety and effectiveness of a medical device, the manufacturer considers whether the device could be safely used on more than one occasion, or whether its sterility or performance would be unacceptably compromised by reuse. Manufacturers who cannot reasonably assure the safety and effectiveness of a medical device for more than one use will label this device "for single use only."

Manufacturers have the duty to protect the public health and the right to avoid unacceptable business liability risks by labeling devices for single use only. The Medical Device Manufacturers Association (MDMA) is concerned that current FDA regulation of the reprocessing of single-use devices is too limited to provide the public with a reasonable assurance of continued safety and effectiveness. We also fear that manufacturers may be unfairly held liable for injuries that result from the unsafe reuse of single-use devices.

On principle, FDA should regulate all similar activities equitably. For example, if an OEM were to collect its own single-use devices from a hospital, reprocess them, and then return the devices to the hospital, FDA undoubtedly would call this an adulteration or misbranding of the devices and would initiate legal or administrative proceedings against the OEM. Why should a commercial third party or a hospital be regulated differently from an OEM if it undertakes a similar activity? After all, FDA has informed OEMs that changing device labeling from single to multiple use generally requires the submission of a premarket notification.

The reprocessing of a single-use device for subsequent reuse changes the intended use of the device and can significantly affect the safety or effectiveness of the device. Therefore, the reprocessor of a single-use device should be subject to the same regulatory requirements as manufacturers. In particular, reprocessors of medical devices must be required to demonstrate to FDA and the public that reused single-use devices are still safe and effective for their intended use.

Many manufacturers have submitted information to FDA on patient injuries and infections caused by reused disposable devices. The federal Centers for Disease Control (CDC) has also investigated the reuse of single-use devices and recognizes that this practice can contribute to hospital-based infections, which cost the American healthcare system nearly $3.5 billion annually. In fact, the CDC's guidelines on hospital environmental controls recommend that "items or devices that cannot be cleaned and sterilized or disinfected without altering their physical integrity and function should not be reprocessed" (CDC, Morbidity and Mortality Weekly Report 36, no. 2 [1987]: supplement). The guidelines also suggest that "reprocessing procedures that result in residual toxicity or compromise the overall safety or effectiveness of the items or devices should be avoided."

Nevertheless, FDA has so far refused to enforce regulations that would protect the public against unsafe reuse of single-use medical devices. Although the agency requires commercial reprocessors to register and comply with its quality system regulation, reprocessors currently are not required to submit any studies to FDA in support of their claims that reprocessed single-use devices are indeed safe and effective for multiple use. For their part, hospitals are not even required to register with FDA, much less comply with any standards or protocols for reuse. How, then, can we ensure that patients are not harmed by reused single-use devices?

At the very least, FDA should fulfill its mission of protecting and promoting the public health by requiring healthcare facilities and commercial reprocessors to demonstrate that the single-use devices they reprocess and reuse are still safe and effective. The agency should also require all reprocessed and reused single-use devices distributed by third parties to be labeled as "used and reprocessed," so that practitioners and patients are aware of the nature of the devices they are using or being treated with.

This shouldn't be too much to ask of FDA. After all, many commercial reprocessors suggest that the used devices they attempt to clean and sterilize are indeed safe and effective for further use. For instance, one leading reprocessor claims on its Web site that it can reprocess medical devices with "total safety" for patients. Furthermore, the firm maintains that "each device is 100% performance tested using thorough visual and functional cross-inspections."

If commercial reprocessors can market their remanufacturing operations this way, then FDA should require these companies to prove their claims by submitting premarket notifications with supporting clinical data. No manufacturer of a medical device would be allowed to make statements about the safety and effectiveness of a device for its intended use without receiving the appropriate clearance or approval. Why should commercial reprocessors be permitted to evade this standard?

MDMA and its member manufacturers will continue educating healthcare facilities and consumers about the dangers involved in the reuse of single-use devices. However, manufacturers can only do so much to protect patients against unsafe reuse.

It's up to FDA to step in and enforce its regulations. The risks inherent in any surgical procedure, for example, are real enough. Should patients also have to worry about whether the very devices used in that procedure could injure or infect them?

Stephen J. Northrup is executive director of the Medical Device Manufacturers Association (MDMA), a national trade organization based in Washington, DC, that represents approximately 130 independent manufacturers of medical devices, diagnostic products, and healthcare information systems.


Copyright ©1999 Medical Device & Diagnostic Industry

Lightening the Regulatory Burden : Does FDA's Export/Import Guidance Go Too Far? : Focus on Risk Management : In Europe, FDA Will Abide by FOIA : FDA Updates Consensus Standards Guidance : Old Won't Fit into New : Device Firms Need Design Control Procedu

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI March 1999 Column

Defining "least-burdensome" concept is turning out to be quite a burden.

Also:

  • Does FDA's Export/Import Guidance Go Too Far?
  • Focus on Risk Management
  • In Europe, FDA Will Abide by FOIA
  • Old Won't Fit into New
  • FDA Updates Consensus Standards Guidance
  • Device Firms Need Design Control Procedures
  • Henney Revamps Commissioner's Office
  • Deputy Commissioner Schultz Leaves

Reversal of the Kessler-era mission to "take science up a notch" at CDRH may be the new policy direction under the FDA Modernization Act (FDAMA)—but don't expect anyone to actually say so.

Instead, industry presentations to a January FDA public meeting—and careful reticence on the part of FDA officials—seem to invite the assumption that FDAMA's section 205 now relieves industry of the need to provide clinical evidence of effectiveness for a premarket approval (PMA) device or extensive other data for a premarket notification (510(k)) device, except in unusual cases.

Section 205, popularly dubbed the "least-burdensome" rule, requires FDA to "consider" reducing the extent of data to be required "through reliance on postmarket controls," and, with respect to clinical data that may be needed, to "consider, in consultation with the applicant, the least-burdensome appropriate means of evaluating device effectiveness that would have a reasonable likelihood of resulting in approval."

That's pretty explicit, but it still leaves wiggle room for bureaucrats. All Congress can do is direct FDA to consider—it can hardly order it to heed or follow. This sobering reality is what provoked the two main industry groups, the Health Industry Manufacturers Association (HIMA) and the Medical Device Manufacturers Association (MDMA), to each draw heavily in recent pronouncements on the same solitary word that lawmakers and others have been pointing, post-FDAMA, like a weapon at FDA's head: spirit, as in "the letter and the spirit of the law."

FDA officials have not been using that word very much themselves as they review their options, but new commissioner Jane E. Henney has used it a lot in assuring FDAMA's principal architect, Labor and Human Resources Committee chairman Senator James Jeffords (R–VT), that her top priority will be to implement FDAMA fully, in the way Congress intended.

In January, the two industry associations criticized heavily FDA's Kessler-era tendencies of requiring more and ever-deeper scientific and technical data for device applications. The groups extolled section 205 as both a restatement of Congress's long-standing mandate to avoid overregulation of devices and the cornerstone of the entire legislation.

HIMA announced that it would facilitate an all-parties task force to look at situations in which randomized trials are unnecessary to demonstrate effectiveness. The task force also will examine ways to help refine FDAMA's "least-burdensome" effectiveness concept in various device contexts such as vagus nerve stimulators, antimicrobial-coated cardiovascular implants, a breakthrough therapeutic device, and a diagnostic device intended to diagnose a life-threatening disease or condition.

The task force will then develop a general protocol for use by each Office of Device Evaluation division in determining the least-burdensome valid scientific evidence. The protocol will include detailed written procedures and accompanying flowcharts for determining the least-burdensome approach. MDMA, for its part, stressed that the onus is on FDA to cease its use of randomized clinical trials as a default requirement, and that a meaningful procedure for dispute resolution needs to be established.

FDA maintains that its draft guidance for industry on exports and imports under the FDA Export Reform and Enhancement Act of 1996 reflects current practices to the extent that they exist and meets the needs of the various centers. Industry representatives aren't so sure.

Comments submitted by HIMA claim there are portions of the guidance that seek to establish additional requirements and therefore need to be deleted. As an example, it cited recommendations on how a manufacturer can demonstrate that a product does not conflict with the laws of the importing country and is not sold or offered for sale in the United States. In each instance, HIMA says the agency is being overly restrictive in its guidance, while agency officials say the guidance sets forth past practices yet is flexible.

Whereas FDA suggests that a company obtain a letter from a foreign government agency stating that the product has marketing approval in that country or does not conflict with the country's laws, HIMA responds that statutory language does not restrict the methods by which such demonstration is to be made.

CDRH's deputy director for program operations, Wes Morgenstern, states that FDA has "always told firms that they must obtain permission from a government official if such permission can be obtained." He added that CDRH maintains a list of countries that won't cooperate with the requirement and tells manufacturers to check the list and report if they are having problems getting an approval letter, whereupon FDA will allow an alternative.

Another bone of contention is the guidance's suggestion that, in order to show that a product is not sold or offered in the United States, a firm could submit a label stating "Not for sale in the United States." But HIMA retorts that such a practice would turn the demonstration into a mandatory labeling requirement. Morgenstern says the label idea was just an option: "The primary means of proof should be careful records. The company should have very good records that show what goes in and what comes out. It's as simple as that."

CDRH's Office of Compliance is planning a series of industry training seminars that will focus on risk management. Risk management covers everything from device design to manufacturing to marketing. Training will emphasize total risk management, and not focus simply on design control. There are many areas in the regulations that require risk-based decision making, and companies will need statistical tools and science-based techniques to comply. AAMI is also working on standards for risk management.

Under the recently concluded Mutual Recognition Agreement (MRA) with the European Union (EU), any information collected for FDA by an MRA partner that would be releasable under the U.S. Freedom of Information Act (FOIA) if gathered in the United States will in fact be subject to release by FDA under that statute.

That is one conclusion drawn from dozens of pages of FDA correspondence prepared in response to scores of questions from the House Commerce Oversight and Investigations subcommittee. However, unlike home-ground inspections, FDA will only get documents from EU members if it explicitly requests them in each case.

The question of FOIA document release was a potential deal breaker that threatened to wreck the MRA at one point, but the Europeans relented after their local industries agreed to yield to U.S. practice and law in order to consummate the agreement.

On trade-secret protection, however, FDA yielded to local laws about which it knows little. "Samples and analytical data will be handled according to the laws of the country in which the material was collected," FDA told the subcommittee. The agency said that each party to the MRA would use its current procedures to determine what is trade-secret information. The MRA, it added, "directly addresses sharing of inspection reports, not other types of 'evidence,' during the operational period."

The correspondence with the subcommittee makes plain that, although FDA won on FOIA, it signed the MRA with little knowledge about the equivalency of various EU regulatory systems that will be crucial to the MRA's success. Addressing the accountability of its counterpart agencies in the EU, FDA said it "does not know to whom member-state regulatory authorities answer, but it will closely examine this during the transition period and thereafter." The agency also said it does not know all the member-state laws that may be used to remove products from the market, but noted that under Article 13 of EEC Directive 91/35, six member states "may rely on complaints and mandatory recalls." FDA said it would determine whether this provides equivalent protection from unsafe products.

In addition, FDA professed ignorance as to whether there are different standards in EU countries for companies that are owned in whole or in part by sovereign governments but said it "intended to consider this issue when conducting its equivalence assessments." The question is important, because one criterion for assessing equivalence is the avoidance of conflicts of interest—for example, would a government that owns its own drug company be equivalent to FDA when it inspects that company for FDA?

"At this time," the agency said cagily, "FDA is not in a position to speculate whether this issue would preclude a particular regulatory authority from being determined equivalent." FDA also acknowledged that the MRA does not define conflicts of interest, so FDA will use its own codified standards when assessing EU regulatory agencies for such conflicts.

FDA has expanded its guidance on "Frequently Asked Questions on Recognition of Consensus Standards" to help device manufacturers with abbreviated and special 510(k) submissions under CDRH's new paradigm.

When it comes to FDA's new quality system design control regulations, device companies are finding that old ways aren't convertible.

According to GMP and quality systems expert Kim Trautman at CDRH, field investigators in the first six months of auditing have found that too many firms are trying to superimpose their existing engineering change control order and notice systems onto the new regulations.

Trautman said that when firms use existing change control orders or notices, they are not tying back to the design control requirements as they should, "so there are a lot of linkages and ties that are missing."

According to Trautman, change control orders and notices are very strict systems attuned more to documents and drawings, making them harder to fit to concepts or to improvements to devices. "People are trying to fit something they are comfortable with into something that needs to be broader and more flexible."

In auditing design control requirements, FDA has so far been lenient. Trautman estimates there have only been six warning letters covering design control violations, and they have targeted only the most egregious violators—firms that did not have any design control procedures at all. It appears that FDA recognizes that there is still a learning curve for everyone, including the agency itself, says Trautman, and will be content for now to focus on serious violators.

FDA Cincinnati District compliance officer Lawrence E. Boyd says medical device companies that have not yet done anything to comply with new quality system design control regulations should develop procedures for implementing the regulations if they want to avoid a warning letter. "They should have a plan to describe how they'll do it," he says, "and specifications for how they will change a design if that's necessary." Warning letters have been sent to a half-dozen firms nationwide that had not addressed the regulations at all since the June 1, 1998, start of design control audits. One of those letters was sent in December to Scottcare Corp. Inc. (Cleveland), which, according to Boyd, was the most egregious violator.

As soon as she arrived at FDA in December, commissioner Jane E. Henney appointed deputy commissioner for strategic management Linda Suydam to head a task force to recommend a new organization plan for the Office of the Commissioner, which had come under criticism for being too large and inefficient. Suydam told FDLI that she and the other three members of the task force—Center for Food Safety and Applied Nutrition director Joe Levitt, the Center for Veterinary Medicine's Bob Sauer, and associate commissioner for planning and evaluation Paul Coppinger—would report to Henney sometime in early 1999.

FDA deputy commissioner for policy William B. Schultz, who had been a candidate for commissioner before Jane Henney was chosen, left the agency effective January 1 to assume a senior legal position in the U.S. Attorney General's office.

Schultz came to FDA in February 1995 at the invitation of then-commissioner David A. Kessler. Schultz's service was warmly praised December 16 by Senate Judiciary Committee chairman Orrin Hatch (R–UT) during a speech at FDLI's Annual Educational Conference. Hatch said that while he "often disagreed" with Schultz, the latter possessed "integrity, knowledge of the law, tenacity, work ethic, ability to reach compromise, and . . . absolute devotion to advancing the interests of the public."

Schultz had previously been counsel to the House subcommittee on Health and Environment, and before that served 13 years with Ralph Nader's Public Citizen Litigation Group.


Copyright ©1999 Medical Device & Diagnostic Industry

Fashion Platelets: New Coats for Coronary Stents

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI March 1999 Column

R&D HORIZONS

Complications associated with the use of coronary stents provide the opportunity for better devices through surface modification.

Coronary atherosclerosis is caused by fatty deposits called plaque that narrow the cross section available for blood flow through the coronary arteries, which supply blood to the muscle of the heart. To treat patients with this condition, cardiac surgeons often use a procedure called coronary artery bypass grafting (CABG). Typically, the saphenous vein is harvested from the patient's leg, trimmed to size, and grafted to the artery, thus bypassing the blockage. Although generally effective, the procedure carries risks ranging from infection to death and usually involves painful closure wounds.

Under certain circumstances, interventional cardiologists choose to treat the blockage rather than bypass it, using a minimally invasive technique called percutaneous transluminal coronary angioplasty (PTCA). In PTCA, a catheter is typically inserted through the femoral artery in the patient's leg, threaded into the blocked coronary artery, and inflated. The plaque is compressed into the vessel wall and the lumen or flow cross section of the artery is thus enlarged. A less common technique called directional coronary atherectomy (DCA) can be used in conjunction with or instead of PTCA to literally cut plaque from the wall. To treat calcified coronary arteries, a related technique called rotational coronary atherectomy (RCA) can be employed to remove calcified plaque with a high-speed rotating burr. Unfortunately, the body's response to these procedures often includes thrombosis or blood clotting and the formation of scar tissue or other trauma-induced tissue reactions—for example, at the PTCA site. Statistics show that restenosis or renarrowing of the artery by scar tissue occurs in fully one-half of the treated patients within only 6 months after these procedures.1

To prevent restenosis, cardiologists often place a small metal tubular device called an intracoronary stent at the PTCA site. An intravascular ultrasound guidance system is sometimes used to optimize stent placement. Results of several clinical studies suggest that the rate of restenosis is significantly reduced in certain indications by the use of coronary stents. Among the first published studies, the Benestent and Stent Restenosis Study (STRESS) trials reported restenosis rates of 33% and 25%, respectively, with coronary stenting.2 A subsequent study reported that 11% of patients with acute myocardial infarction who received stents experienced restenosis, compared with 34% in the PTCA-only group.3

THE STENT MARKET

While the trend toward consolidation of medical device markets continues, the fast-growing U.S. coronary stent market still represents an attractive opportunity for stent manufacturers. Johnson & Johnson (J&J; New Brunswick, NJ), which holds a key patent applicable to inflation-deployed stents, dominated the market for a period following the introduction of its Palmaz-Schatz stent in 1994. J&J subsequently licensed the technology to some of its competitors, including Medtronic Inc. (Minneapolis). Other manufacturers challenged the patent, and litigation remains in process.

Figure 1. Guidant's ACS Multi-Link Rx Duet coronary stent system. (Photograph courtesy of Guidant.)

Upon its introduction to the market, the GRII stent produced by Cook Inc. (Bloomington, IN), which was approved by FDA in May 1997, competed well with the Palmaz-Schatz, due in part to a successful pricing strategy. The ACS Multi-Link, approved October 1997 from Guidant's Advanced Cardiovascular Systems (ACS; Santa Clara, CA), and the Micro-Stent II and gfx stents, approved December 1997 from Arterial Vascular Engineering (AVE; Santa Rosa, CA), gained rapid market acceptance to become the current domestic market leaders (Table I). Boston Scientific (Natick, MA) appeared well positioned to challenge the market leaders with its NIR ON Ranger stent (approved August 1998) featuring an over-the-wire (OTW) delivery mechanism and SOX securing system, but the company voluntarily withdrew the product from the market in October 1998 because of reported balloon leaks in a few devices. Medtronic's coiled tantalum Wiktor stent (approved June 1997) has garnered a limited share of the market, and the company's beStent is expected to receive FDA approval in 1999. Guidant hopes to maintain market leadership with its latest entries, the ACS Multi-Link Rx Duet and ACS Multi-Link OTW Duet coronary stent systems (approved November 1998), which the company claims provide a wider range of sizes, lower profiles, greater deliverability, and enhanced radiopacity (Figure 1). The dynamic nature of the stent market is evidenced by how much information becomes out-of-date during the short time during which articles on stents are in press.

CompanyProduct Name
and Type
FDA
Approval
Date
1998 U.S.
Market
Share (%)
Arterial Vascular Engineering Micro Stent II & gfx
Stainless-steel coil and ring
December 1997 23
Boston Scientific NIR ON Ranger
Stainless-steel slotted tube
August 1998 8
Cook GRII
Stainless-steel slotted tube
May 1997 13
Guidant ACS Multi-Link
Stainless-steel slotted tube
October 1997 42
Johnson & Johnson Palmaz-Schatz Crown
Stainless-steel slotted tube
1994 13
Medtronic Wiktor
June 1997 8


Table I. U.S. coronary stent market share in 1998 (annualized). (Source: Clinica World Medical Device and Diagnostic News 831, October 26, 1998.)

STENT DESIGNS

Most stents are configured as a slotted tube fabricated from a malleable metal such as stainless steel (Figure 2). Such stents can be placed on an expandable balloon delivery catheter. Other stents are made of wire mesh or a self-expanding metal such as Elgiloy or nitinol compressed into a coiled configuration and held by a sheath over the tip of a catheter. To make the tortuous journey to the blocked artery, stents are delivered in the collapsed condition. When the delivery catheter tip that retains a stent arrives at the site of the lesion, either the balloon is expanded to cause plastic deformation of a malleable stent or a self-expanding stent is released from its sheath. Either action results in the stent pressing firmly against the inside of the artery wall.

Figure 2. 1997 version of the Palmaz-Schatz Crown stainless-steel slotted tube stent. (Photograph courtesy of Johnson & Johnson.)

Typically, there is some contraction of the artery wall, decreasing the lumenal diameter, that occurs immediately after PTCA. The skill of the cardiologist often determines the success of the procedure, since the degree of stent penetration into the vessel wall affects restenosis. The Multicenter Ultrasound Stenting in Coronaries (MUSIC) trial reported less than 10% restenosis in patients whose stents were delivered using an ultrasound guidance system; this low rate could perhaps be due in part to the highly skilled and very experienced cardiologists involved in the study.4

Numerous studies suggest that most of the current popular designs of intracoronary stents are functionally equivalent. The Nirvana trial found no difference between the Palmaz-Schatz and NIR ON Ranger stents in the rates of restenosis or major adverse cardiac events.5 Whereas acute complication rates differed, the SMART trial found no difference in long-term outcomes between the Palmaz-Schatz and Micro-Stent II stents.6 Presentations at the 1998 annual meeting of the American College of Cardiology further support these conclusions. Despite using different restenosis criteria, both a study of 1147 patients that randomly received one of five different stents and a review of five paramount studies found little effect of stent type upon 6-month rates of restenosis and major adverse cardiac events.7,8 However, some stents were reported to be easier to deploy than others.

SURFACE MODIFIED STENTS

Although the use of coronary stents is growing, the benefits of this use, compared with alternative treatments, remain controversial in certain clinical situations or indications, and the complications of coronary stenting—including thrombosis and restenosis—allow room for significant improvement in product performance. Surface modification of stents may provide a solution to both of these adverse effects while simultaneously leading to real product differentiation.

Aside from new designs, the technology with greatest potential to differentiate the next generation of stents may be in the area of nonthrombogenic and anti-cell-proliferative coatings. Two approaches are in or near commercialization: immobilization of antithrombotic/antirestenotic ligands, and delivery of antithrombotic/ antirestenotic drugs. Alternatives including gene and radiation therapies may soon follow. Surface-modification techniques are integral to each of these approaches, either directly (modification or coating with an active agent) or indirectly (as a delivery vehicle).

Two ligands that have been proposed as decreasing thrombosis and restenosis are phosphorylcholine (PC; Biocompatibles, Farnham, Surrey, UK) and heparin (HEP; Carmeda, Stockholm). HEP is an antithrombotic compound that works by interfering with blood coagulation through a specific interaction with thrombin, a promoter of coagulation.9 Clinically, the drug is often administered intravenously and its effects persist with a half-life of up to several hours. However, because of steric effects, immobilized HEP is less susceptible to enzymatic degradation than is circulating heparin. Medtronic first immobilized HEP for use in blood oxygenator circuits, and later for use with stents.10

Because the outer surfaces of blood cells are composed primarily of phospholipids, Chapman and Charles proposed that modification of polymers with PC would improve hemocompatibility in clinical devices.11 Unlike the case of heparin, the mechanism for PC nonthrombogenicity appears to be nonspecific and is not well understood. The reported blood compatibility of PC may be related to the observation that little protein from the blood adsorbs on PC compared with blood-protein adsorption on typical stent metals. However, other phospholipids repel proteins equally well yet are more thrombogenic. Perhaps the key is in the way that PC binds proteins from blood.

Animal studies with modified stents have provided both encouraging and disappointing results. In the baboon arterial-venous (AV) shunt model, minimal adhesion of blood platelets—the "cells" that adhere to damaged blood vessels and facilitate formation of a blood clot—was reported on stainless-steel shunts coated with PC, as were decreased platelet adhesion and blood coagulation in vitro.12 Hanson and Chronos subsequently compared stainless-steel stents coated with HEP or PC in the baboon aorto-iliac model.13 Markedly reduced thrombosis on coated stents harvested 1 month after placement resulted in up to a one-third reduction in neointimal area (the tissue that grows into the vessel and reduces the area available for blood flow) compared with the uncoated control (Figure 3). Unfortunately, however, no difference was noticed in coated stents harvested 90 days after placement.

Both reduced subacute thrombosis (less than 1 week) and a reduced restenosis rate were reported in the Benestent-II clinical trial of Palmaz-Schatz stents coated with HEP, but better (higher-pressure) deployment and a better drug regimen compared with historical studies were also used in the trial, complicating comparisons between coated and control devices.14 It should be noted that reduction in subacute thrombosis may justify HEP or PC treatment of stents because of the large financial cost associated with treating thrombosis (e.g., catheterization, restenting, intensive care, etc.). However, the baboon-model results cast doubt on the long-term benefit of HEP with respect to long-term restenosis. Also, there are concerns that the presence of immobilized HEP may delay repopulation of the damaged vessel with the endothelial cells that normally line a healthy vessel. Another concern is heparin-induced thrombocytopenia, a condition characterized by abnormally low platelet numbers in the bloodstream and thromboembolic complications (detached clots that block blood flow through smaller vessels).

J&J has not yet introduced its HEP-modified stent despite encouraging published test results; Medtronic launched its HEP-coated Wiktor-I stent system in Europe and other international markets in April 1998. Others are attempting to commercialize the concept as well—for example, Biocompatibles launched the divYsio PC-modified stent, also outside the United States. While J&J and Biocompatibles once considered a more extensive relationship, they may be collaborating on combination drug/PC coatings in an attempt to achieve zero restenosis, as the PC coating makes an excellent drug-delivery vehicle.15 However, it is not obvious which drugs will be necessary and whether adequate quantities can be loaded into the PC coating.

Figure 3. Effect of phosphorylcholine surface modification of divYsio stents (Biocompatibles) upon neointimal area 1 month after placement in the baboon model. (Photographs courtesy of Stephen R. Hanson, PhD, and Monique Marijianowski, PhD, Emory Univ., Atlanta.)

A much simpler approach that has also been proposed is using pure gold as a hemocompatible coating material.16 Gold offers increased fluoroscopic visibility and potentially decreased thrombosis relative to stainless steel. Whether or not gold coatings reduce the intimal hyperplasia or excessive tissue growth at the stent-vessel junction remains to be demonstrated. Nonetheless, several companies are developing gold-coated medical devices, including coronary stents.

FUTURE TECHNOLOGIES

Another potential solution to preventing restenosis involves local delivery of various compounds that affect cell function, including antiplatelet agents, anticoagulants, calcium agonists, antiinflammatory drugs, antiproliferative drugs, hypolipidemic agents, and angiogenic factors. Polymers such as silicone rubber and certain hydrogels, when applied to stents, may serve as appropriate delivery vehicles potentially superior to PC. Degradable polymer systems such as poly(glycolic-co-lactic) acid (PGLA) could possibly be used. Gene and antibody therapies delivered from stents are also being developed.

One strategy amenable to local drug delivery for preventing restenosis involves administration of a blood clot–inhibiting drug to the patient during and after the procedure. Like heparin, the drug ReoPro (Centocor Inc.; Malvern, PA) inhibits blood clotting, albeit by a different mechanism. Although clotting inhibits bleeding and initiates the body's vessel-repair process, it may also facilitate restenosis of coronary arteries after PTCA or stent placement. ReoPro binds to the surface of the platelet at the site that must be expressed or physically accessible in order for the platelet to bind to damaged vessels. By preventing platelet adhesion at the stent lesion during and immediately after the placement of the stent, cardiologists hope to prevent restenosis from occurring later.

In the Evaluation of IIb/IIIa Platelet Inhibitor for Stenting (EPISTENT) trial, ReoPro was administered to patients in conjunction with PTCA and/or stent placement. Adverse events 30 days after PTCA were reported to be lower in ReoPro patients—a 51% reduction with stenting and a 36% reduction without stenting.17 Delivery of ReoPro from the stent itself could prove to be an even more effective strategy.

Perhaps the most interesting approach to prevention of restenosis is radiation therapy. Several manufacturers are developing a radiotherapy approach, using either an acute single dose or prolonged staged delivery. In the case of acute delivery, a dose of radiation is delivered to the vessel from a catheter at the time of intervention, with the goal of inhibiting excessive growth of tissue at the site of stent placement. (When exposed to a certain types of high-energy radiation, cells that might otherwise overproliferate and cause restenosis become quiescent or die.) This method may be the preferable technique, as exposure of both the surgical team and the patient to the radiation can be minimized. Use of beta radiation—emitting isotopes, which are easily shielded, also limits exposure of the surgical team while readily delivering the required energy to the lumen of the treated artery. (For example, the Novoste Corp. [Norcross, GA] Beta-Cath single-dose system houses a strontium-90/yttrium 90 beta emitter.)

In staged delivery, a radioactive source is incorporated into the device itself. Radiotherapy can be used in conjunction with both PTCA and stent placement and may be useful for reopening blocked stents. Guidant's clinical trial, the Proliferation Reduction with Vascular Energy Trial (PREVENT), and Novoste's BRIE marketing trials are in progress in Europe.

CORONARY STENTS REDUCE INCIDENCE OF EMERGENCY PROCEDURES

According to a recent study, using coronary artery stents to stabilize patients who encountered complications during coronary artery angioplasty helped reduce the number of emergency surgeries performed. The reduction in the number of surgeries saved money and should allow hospitals to forego the practice of keeping cardiovascular surgeons on standby each time cardiologists perform angioplasties, which would further decrease costs.

"More and more, we are seeing problems that were once corrected only by surgery that are now treated with less-invasive technologies," explains Mike Wagner, a resident in general surgery at St. Luke's Hospital (Bethlehem, PA), where the study was conducted. "Unfortunately, complications incurred during these less-invasive procedures often require urgent surgical intervention."

Statistical analysis showed that while 2–5% of percutaneous transluminal coronary angioplasty (PTCA) patients typically undergo emergency coronary artery bypass grafting (CABG), stent use reduced the number to 1.4%. The study, conducted from 1992 to 1997, involved 2849 patients who underwent PTCA. Of the 505 patients who underwent the procedure before the stents were widely available, 14 (2.9%) required emergency surgery, whereas only 32 (1.4%) of the 2390 patients for whom stents were an option required emergency CABG.

According to the study, stent use prevented 37 emergency bypasses and saved approximately $1.2 million. Because the stents often dilated arteries enough to eliminate the original risk of a blocked artery, many patients who received stents not only avoided an emergency procedure but avoided surgery altogether.

For those patients who did eventually undergo the CABG procedure, the option of handling the surgery on an available rather than an immediate basis allowed time for patients to stabilize, a fresh surgical staff to be assembled, and an operating room to be scheduled.

"The study didn't answer how many of these angioplasty patients will need surgery eventually," Wagner explains. "What it did answer was whether we could reduce the number of emergency CABG surgeries that needed to be performed, given the increased mortality risk that accompanies such emergency intervention.

What it boils down to, says Wagner, "is the cost-benefit ratio. Eventually there will be some loss of life when a cardiovascular surgeon and an operating suite are not kept immediately available, but even having that doesn't guarantee that a patient will be saved. What we need to do in medicine is find the acceptable risks, and this study certainly did that. Furthermore, cardiovascular surgeons, no longer under the burden of having to be immediately available, are better able to perform their other patient-care responsibilities." —Jennifer M. Sakurai

CONCLUSION

The coronary stent market is among the fastest growing U.S. medical device markets. As more devices are approved by FDA in the near future, market leaders Guidant and AVE will face the challenge of increased competition. Although coronary stenting has undoubtedly benefited thousands of patients, thrombotic and restenotic complications associated with the procedures offer manufacturers the opportunity to enhance product performance. Some improvements will be made with new designs, and surface-modification techniques adapted to the current generation of devices hold great promise. Immobilization of PC and HEP ligands is feasible today, and local delivery of pharmaceutical agents from applied surface coatings appears to be on the horizon. Concurrent strategies such as radiotherapies and administration of antiplatelet agents during interventional procedures may also help alleviate complications associated with stent placement.

REFERENCES

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Joe Chinn is a staff scientist and Jeff Mabrey is a product manager with Sulzer Carbomedics (Austin, TX).


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