BB&T National Editor

PALM DESERT, California — What are the ingredients that make high-technology higher than, say, just ordinary, everyday technology?

Is it a matter of advanced and most complex medical applications? The newest materials and combination(s) of materials? The most difficult feats of engineering? The most sophisticated research?

The answer of course is probably some, if not all, of these elements — and throw in a whole other level of complexity in terms of associations with interfacing high-tech products and new, sophisticated methods and procedures for testing.

The increasing complexity of medical device products, what they are made of, how they are made and how they withstand the rigors of testing as they make it to market, were some of the subjects addressed at the 2007 Materials and Pro-cesses for Medical Devices (MPMD) Conference. In this venue, the titles of the conference sessions were not particularly "catchy." But they were long on drill-down types of information for the materials engineers and product designers who made up most of the roster of attendees. Among the straightforward titles: Advanced Materials, Corrosion Engineering, Fabrication Processes, Fatigue Life, Materials Information and Selection, Materials R&D, Regulatory Affairs Related to Materials, and Surface Engineering; and they generally were presented to standing-room-only meeting rooms.

Testing for fatigue

The Fatigue Life I and II sessions included presentations on topics such as "Statistical Methods for Life Prediction in Medical Devices," "High-Cycle Fatigue Evaluation of Two Beta-Rich Titanium Casting Alloys" and "Durability Test for Patella Implants."

In his "Statistical Methods" presentation, Hengchu Chao, PhD, an engineer in the heart valve therapy unit of Edwards Lifesciences (Irvine, California), noted the importance of materials fatigue in device performance. He cited several important tests, including fatigue testing of a device under service load, testing to success to demonstrate reliability, and testing to failure to establish a performance curve.

Chao said such testing provides clear interpretation of results, a platform for long-term testing, and a basis for re-testing for different sizes, dimensions and processes. Among the important design criteria in such testing, he said, is to evaluate a material's reliability vs. safety factors.

He noted that test-to-success on an actual device "provides clear evidence" of product performance, while, for instance, test-to-fracture "provides valuable information on failure reads." Chao added that the life-analysis testing approach "provides a statistical basis for fatigue life predictions," while stress-analysis testing "mimics product service conditions."

Proper testing design, including a fatigue/life parameter, "allows a good prediction of device performance," a prediction he said allows a clear "Go!" or "No!" message in evaluating whether a proposed design iteration should go forward. He said a well-developed test-for-success on an actual device "is a useful confirmation to life-analysis testing."

Jeremy Schaffer of Fort Wayne Metals Research Products (Fort Wayne, Indiana), discussed fatigue life in medical-grade wire, listing a hierarchy for this type of testing (Table 3).

As an example of a difficult testing problem, Schaffer discussed the use of 35Co-35Ni-20Cr-10Mo fine wire, a material with roots back to 1965 when it was first developed as an aerospace fastener alloy. "It began being used in medical devices in the 1970s and 1980s," he said, adding that the alloy was prized for "its resistance to corrosive attack and fatigue."

In 2003, a "clean melt" version was introduced, leading to the wire's development for cardiac rhythm management (CRM) lead wires, coils and sensing elements.

"Do they fail?" he asked rhetorically, raising the central question of the session, answering, "Eventually, yes." He went on to cite the importance of the physical location of a lead as key to its length of life.

"These are very small products," he said, "most being less than 1 mm in diameter," providing difficulties in failure analysis. "They generate microscopically small crack effects."

Schaffer said that testing brings evidence of "lots of characteristics, but fatigue failure is the one that stands out."

Particular testing for particulates

Another testing issue in the "small products" category is the testing of drug-eluting stents (DES), in particular the finding that these devices are associated with particulates that may be one source of adverse events.

Dr. James Conti, executive VP of Dynatek Dalta Scientific Instruments (Galena, Missouri), discussed methods for evaluating the shedding of particulates by DES. Conti said that particulates, those from DES devices as well as, also, from orthopedic implants, "size matters." And: "Smaller particles are more toxic."

The particulate problem is pervasive, Conti said. "If you're dealing with a medical product, you'll be dealing with particulates."

He said bifurcated products, a commonplace approach in the stents realm, "tend to break." So, in the set-up stage, "you need to know that your product is physiologically compliant, and that sanitation issues are addressed." For testing, "you have to set target values and have data-collection methods clearly identified."

Conti said intermittent testing is better than one-time testing, which tends to get short shrift from the FDA. "That allows you to be more stent-specific," he said.

But best of all, in his view, is real-time data collection, which his firm does. "It's the best method," Conti said. "You can tell which stent the data is coming from, which better allows you to interpret the shower of particles."

Providing what patients expect

So how does an orthopedic surgeon, one of the prime end-users of the products that come from the materials and processes being discussed at the MPMD conference, view the state of the industry? Stuart Goodman, MD, PhD, professor of orthopedic surgery at Stanford University (Stanford, California) and a surgeon specializing in hip and knee replacements, emphasized the early stage state of materials development.

He said there is ample room for improvement, particularly in areas involving device wear and the avoidance of debris that can turn a good implant bad.

And he said the key challenge in orthopedics is the development of joint replacements that "last a lifetime and yield normal function."

Citing what he called the "epidemic" of arthritis in both the U.S. and worldwide, he provided the statistics for total joint replacement are pretty amazing.

He noted, for example, in 2003 some 220,000 first-procedure total hip replacements (THRs) were done in the U.S., along with 36,000 revision procedures. Total knee replacements (TKRx) are even more pervasive, with some 418,000 first procedures in the same year. "Patients usually have a very good understanding of the procedure and their expectations," Goodman said. "They've been on the Internet and talked to friends and acquaintances, learning all they can about the procedure they're going to undergo."

And what do those patients want as an outcome? "They want a replacement joint that works like normal," he said. "Can we as surgeons — and as device developers and manufacturers — deliver?" Not completely, he said in response to his own question.

The reason those patients' aspirations and expectations can be only partially met, Goodman said, relates to a variety of societal, patient, surgical and design/materials issues.

A sub-set of societal issues involves what might better be termed political or "policy" questions such as "What does it cost?" and "Who pays for it?"

Goodman said, "New technology is the largest driver of healthcare inflation; we spend a lot of money per patient — most of it private, not public funds."

Add to that a growing elderly population, with the percentage of the U.S. population over the age of 65 hovering now between 12% and 13%, but expected to grow to almost 20% of the total population by 2030. And that elderly population "doesn't sit around in a rocking chair anymore," Goodman said. "They're much more active at an older age than our parents were. They want to do more," he said, and often require joint-replacement procedures in order to be able to do so.

A craze for 'the beef"

Goodman cited minimally invasive surgery as the "latest craze," adding that he has something of a "Where's the beef?" concern about MIS outcomes, but that his query is "Where are the studies?" He said there has been a shortage thus far of detailed studies as to the effectiveness of minimally invasive approaches to THPs or TKRs.

Goodman cited advances in surgical navigation as contributing to more accurate placement of hip or knee prostheses. The latest wrinkle is image-free navigation, with intra-operative localization of specific anatomical "landmarks" helping guide surgeons as they make bone cuts.

However, he noted that in alignment studies involving experienced surgeons on cadavers, "there is an amazingly wide spectrum of results."

Insofar as materials are concerned, he said, "We've come a long way in regard to hip replacement materials since Sir John Charnley pioneered THR with the Charnley prosthesis."

Now one of the highly discussed points of reference in the sector is "gender knees," with several companies producing redesigned products to better accommodate the differences in male/female structure.

"And some of the hottest stuff going on now," he said, "is bearing surfaces. "With younger and younger patients — the average age now for TJR patients is about 60, while 20 years ago it was about 70 — the traditional metal-on-metal prosthesis is generating too much wear."

The leader in the clubhouse in the materials "race" is highly cross-linked, ultra-high molecular weight polyurethane, which Goodman said is very biocompatible, has high wear characteristics and offers greater stability because larger femoral heads are possible.

Responding to a question concerning the likely "winner" among the various materials/processes development efforts currently under way — not necessarily including what he characterized as "our hope [of] being able to reconstruct biologically — Goodman said, "For my money now and in the foreseeable future, metal on plastic probably is the gold standard."

Focusing on orthopedics

While cardiovascular is the med-tech king, orthopedic implants are probably at the top in terms of patient knowledge. Hence, a considerable portion of the conference focus was directed to orthopedic implants, with breakout sessions dealing with the latest in research in these areas.

In one such session, Laura Borgstede of orthopedic implant maker Zimmer (Warsaw, Indiana) discussed durability test methods for patella implants.

"The biomechanical function of the patella is as a pulley, aiding the quadriceps muscle in effecting knee extension," she said. "Although it is not common, failure can occur in all manufacturers' patellas."

With an objective of developing a durability test to determine longevity of patella implants, Borgstede and other Zimmer engineers came up with two testing protocols. One, featuring 219,000 cycles, represented 30 deep squats per day for 20 years — the so-called "Muslim prayer ritual" protocol. The other, at 438,000 cycles, amounted to two "prayer rituals" a day for 20 years. Testing both fibiofemoral extension and lateral sheer load, the protocols test "worst-case conditions," she said.

The tests were done on six samples each of the existing — or predicate — patellar implant design and a proposed new design. The materials involved included a conventional all-polyethelyne (PE) patella and a highly-crosslinked all-PE patella. Of the predicate-design patella samples, five survived to about 35,000 while five of the new-design samples registered 51,000 cycles before failing. Borgstede said the data gathered in the testing showed "clinically relevant" failure results.

In a presentation on a different group's efforts at Zimmer, Devendra Gorhe, an engineer in the metals research area, discussed "MRI interactions with Knee and Hip Orthopedic Implants." He gave a quick primer on MRI, citing the three types of magnets used — static, gradient or radio frequency — and the resulting "image artifacts."

What the engineers were measuring was the specific absorption rate of magnetic output by both knee and hip implants. "Implants," said Gohre, "have different magnetic susceptibility than tissue."

While noting that MRI "can cause local disturbance of the static field near an implant," he said testing indicated that in a typical 1.5 Tesla MRI unit, static field displacement was "minimal." Gohre said that testing of a knee implant system indicated "much less heating" with the RF system.

Materials: picking and choosing

Materials selection was another topic of considerable interest at the conference.

In a session on "Materials Selection for Stents and Cardiovascular Devices," Arthur Fairfull of Granta Design (Cambridge, UK), was the presenter of a paper authored by Neil Morgan of AdvaNiTi Consulting (Wilts, UK).

In perhaps the most interesting single graphic shown during the conference, he noted that the materials used in the first angioplasty procedure, performed in 1964 by Charles Dotter, MD, included a VW speedometer cable, insulation from a cable found in the trash — and guitar strings. So much for high-tech.

Balloon-expandable stents came along in 1985, and in 1994 the FDA approved the first truly commercialized coronary stent, the Palmaz-Schatz.

Morgan's paper noted that as stenting has progressed through design innovation and processing techniques, the choice of structural materials also has progressed.

He cited nitinol as "having a stronghold on the self-expanding stent segment," but added that adoption of new platform materials for future iterations of stents is being widely studied.

Managing design risk

In another materials-selection session, Rameesh Marrey of the Cordis (Warren, New Jersey) unit of Johnson & Johnson (New Brunswick, New Jersey) discussed "Probabilistic Methods for Medical Device Design."

"You want to manage design risk in a realistic fashion," he said, adding that probabilistic analysis methods such as "Monte Carlo" simulations provide a way of understanding risk by generating mathematical distributions for device safety. "These distributions allow predictions of device safety at desired levels of product reliability," Marrey said in the session abstract.

He promoted the probabilistic method over the more commonly used "deterministic," or "worst-case," analysis, which he said can be "excessively conservative," as well as not quantifying the degree of conservatism.

"Probabilistic techniques can be used to quantify and manage design risk," Marrey said. He added that they are "theoretically applicable to any experiment where the input variables are characterized and transfer functions known" and are "consistent with the largest number of input variables."

When it comes to sharing lessons learned in vascular device development, Amr Salahieh, CEO of Sadra Medical (Campbell, California), is your man. Salahieh, one of the keynote speakers at the MPMD conference, spoke from experience garnered while being involved with three start-ups in that sector. After opening with what amounted to career-development tips for the medical device designers and engineers in the audience he switched horses to apply those tips to the real-life world of product development.

Salahieh has been involved in the development of thermal and perfusion angioplasty balloons, minimally invasive cardiac surgical devices, drug-delivery and embolic protection devices, and percutaneous valve repair and replacement products.

He highlighted some strategies for identifying and pursuing product development opportunities, including collaboration with venture capitalists, industry and clinicians in that exceedingly difficult drive to commercialization.

Know strengths/weaknesses

"You have to understand what your strengths and weaknesses are," Salahieh said. "Typically there are many design choices [for the product that may be the end result of your efforts], and you have to choose one based on your business model."

Citing his experience with start-ups, much of it with companies coming out of the Incept incubator, he described first being involved with Embolic Protection (EPI), a company founded in 1999.

EPI was addressing a potential $200 million market, one in which the product would demand significant clinical studies before weaving its way through the FDA 510(k) clearance process.

The question was simple: How to design a better embolic-protection filter. The company's solution, according to Salahieh, "was to make it really simple." EPI kept its focus on the fact that it was developing what amounted to a temporary solution to the debris problems that occur during stent-placement procedures.

"Since the device only needed to work 30 to 40 minutes during these procedures, we only needed to do acute studies, not chronic studies," he said.

What resulted was the Filterwire EX, a relatively simple polyurethane filter to keep wayward debris from causing serious negative cardiac events. A second-generation Filterwire EX built upon the initial iteration to offer what Salahieh termed "a much smaller-profile device."

EPI was sold to Boston Scientific (Natick, Massachusetts) in 2001 for some $160 million and additional milestone payments.

Moving to the next generation

Next up for Salahieh was Sadra Medical, launched in July 2003 with the goal of developing a percutaneous aortic valve. With a potential addressable market of $1 billion and a pre-market approval (PMA) regulatory path.

"The challenge was to improve on a first-generation device that was already on the market," he said. Sadra is developing an aortic valve replacement that can be placed via minimally-invasive methods, which differs sharply from the existing standard of care, open heart valve replacement surgery.

Sadra's product is designed to reduce the risks and morbidity associated with open surgical valve replacement, which it says will provide a therapeutic option for patients who are not being treated today.

Terming the Sadra program "a very difficult project, with a lot of different solutions possible," Salahieh called it "a dream come true for materials developers and designers."

Another Incept-conceived company is SquareOne (Campbell, California), which was founded in 2005. Its focus is what Salahieh termed "a rather simple solution" to the problem of inaccurate stent placements.

SquareOne is developing a flared, stainless-steel stent that he said "mimics the human physiology." Salahieh said the company is "still in the development stage but is making great progress."

'One-stop' for materials

Overall, the Materials and Processes for Medical Devices Conference, held at the Marriott Desert Springs Resort, offered a "one-stop-shopping" event for those interested in what "makes" medical devices.

Laura Marshall, director of business development for medical devices at conference sponsor ASM International (Materials Park, Ohio), which likes to add "The Materials Information Society" to its name, is focused on both materials — particularly on the metals side, but increasingly with an added emphasis on polymers — and processes.

"Our members who are involved in the medical-device sector told us a few years ago that we should develop programs around the needs of medical device designers and engineers," she said. So that's what ASM did, beginning with the first Materials and Processes for Medical Devices gathering four years ago in Anaheim.

Last year the conference took a different turn. In a cooperative program with the Cleveland Clinic, the conference was held in the clinic's venue not far from ASM's headquarters.

"That was a totally different setting for us," Marshall said of the gathering, held not far from the society's headquarters location east of Cleveland. "[Attendees] got great feedback, linked through the clinic's surgeons to patients."

The meeting will return next year to the Cleveland setting.