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Microjaws to Deliver Drugs at Cellular Level

Originally Published MDDI October 2001

R&D DIGEST

A monthly review of new technologies and medical device innovations

THIS MONTH: |Creating Imprinted Gels for Insulin Biosensors | Clay Reduces Permeability of Implantable Polymer Components | Body Simulator Preserves Kidney for Transplant | Nanosensor Detects DNA Without Amplification

Mechanized Microfluidic Device Captures Individual Red Blood Cells

The 20-µm wide microjaws can capture a single red blood cell.

Microscale jaws fabricated from silicon and capable of grasping a single red blood cell have been developed at Sandia National Laboratories (Albuquerque, NM). According to Sandia researchers, the microjaws fit in a microchannel that is about 20 µm wide—about one-third the width of a human hair. As a human blood sample flows through the microchannel, the jaws close, trapping and deforming red blood cells. When the cells are released, they travel on, regaining their former shape and appearing unharmed.

Reports Sandia researcher Murat Okandan, "We've shown that we can create a micromachine that interacts at the scale of cells. We've created a demonstration tool with very flexible technology that we believe will enable many designs and concepts." The device can be mass-produced through computer-chip production techniques, according to the researchers. Ultimately it may be used to puncture cells and inject them with DNA, proteins, or pharmaceuticals.

The punctured cells do not need to be blood cells but could be, for example, stem cells, according to Okandan. He explains, "There is an incredibly wide array of applications that can be addressed using this technology—where we can operate at a cellular, even subcellular level, and be able to do it in large numbers to obtain the required statistics on cell populations. [Various] types of sensors, devices for drug discovery, drug-delivery tools, neural prostheses, and research tools are some of the immediately visible applications."

Describing some of the potential advantages of the technology, Okandan says, "This would be a continuous-flow device, which lends itself to massively parallel processing. It could reduce the cost associated with labor-intensive manual operations and enable transfection of cells or cell lines that do not survive other methods, such as electroporation or chemical methods."

The prototype device offers the possibility of performing a considerable level of mechanical intervention at the cellular level because it operates rapidly and is small enough to allow a number of units to operate in parallel in a relatively compact area. According to Sandia, 10 complete units fit in an area smaller than a household electric plug prong, and each device can puncture 10 cells per second.

Jay Jakubczak, deputy director of MEMS Microsystems at Sandia, describes the device as resembling a cellular Pacman. He says, "The technology used to create the microjaw prototype is an advanced surface micromachining technology developed at Sandia. It is a silicon-based technology, compatible with typical IC processes and tools, incorporating five levels of polysilicon that represent the mechanical portions of the device."

Says Jakubczak, the Sandia technology, SUMMiT, is "the most advanced surface micromachining technology in the world and is being applied to enable silicon monolithic integrated microfluidic systems." He adds that, "This technology is applicable to the manufacture and integration of silicon-based microscale pumps, valves, channels, mixers, separation columns, and sensors."

Eight microfluidic devices fit on this tiny module, shown on a soda straw.

The researchers are currently attempting to determine whether the captured red blood cells can absorb a fluorescent material that the group has already shown is naturally rejected by the cells. If the material is readily absorbed, it means that the Sandia scientists have succeeded in creating the first reported example of a continuous-flow, mechanical cellular-membrane disrupter.

The group also hopes to replace the microteeth with hollow silicon needles that are now in development. "The needles would rapidly inject DNA, RNA, or proteins (including drug molecules) into living cells at precise points of their anatomies and in large numbers, possibly changing the course of a disease or restoring lost functions," according to Sandia.

Current methods of cell implantation use electroporation, the application of electric fields to open cell walls for chemical absorption. A problem with this method is that it causes a significant portion of the cell populations to die. Other manual methods exist that use a very fine pipette to deliver genetic material into individual cells—a labor-intensive and specialized process. The Sandia device has the possibility of overcoming both of these problems, the researchers say.

Imprinted Gels May Provide Intelligent Drug Delivery

An estimated 700,000 type-I diabetics in the United States must take insulin, either by injecting themselves with a needle at least twice a day or by using a battery-operated insulin pump. Development of sensing systems that could monitor blood glucose levels and effectively control insulin delivery would benefit many of these patients.

Now, researchers at Purdue University (West Lafayette, IN) are creating a biological sensor for glucose that could ultimately simplify diabetes treatment. The researchers suggest that the technology could help the development of intelligent drug-delivery devices that could be implanted in the body to administer medications such as insulin.

The technique entails forming a mesh-like biomimetic gel that contains glucose molecules. A slightly acidic chemical is then used to remove the glucose and create spaces where the glucose used to be. According to the researchers, if the gel is placed in a liquid such as blood, glucose in the liquid diffuses into the gel and binds to the empty spaces. In this way, the gel is imprinted for glucose molecules.

The research was presented in August at the American Chemical Society's national meeting by Purdue chemical engineering doctoral student Mark Byrne. Byrne is working on the project with Nicholas A. Peppas, Purdue's Showalter Distinguished Professor of Chemical and Biomedical Engineering, and Kinam Park, professor of pharmaceutics and biomedical engineering.

In essence, the approach attempts to mimic the manner in which certain molecules attach to binding sites on other molecules. Such binding is critical to various biological processes. Byrne explains, "Essentially, we are trying to design what nature has done so well, and that's a difficult thing to do. We are creating artificial binding sites."

The researchers suggest that medical devices implanted inside the body could eventually rely on artificial sensing mechanisms that would incorporate a meshwork containing medications. Sensing glucose in the blood would automatically trigger the meshwork to expand, opening pores and releasing insulin or a medication that would enable the body to more efficiently absorb insulin.

Says Byrne, "At this time, we have been successful in creating a polymer gel that can bind glucose molecules. This is the first step (i.e., recognition) in designing an intelligent drug-delivery device that can modulate the release of insulin or other medications in the treatment of diabetes." He adds, "What we have created so far would be involved in the recognition/release action of the overall device."

Explaining how the imprinted gels would act as the recognition/release part of the overall device, Byrne says, "By forming a polymer network in the presence of particles that can bind glucose, a sensitive network that swells with glucose in solution (and [triggers] a diffusive release of insulin from the meshlike matrix) and contracts (no insulin release) when glucose is not in solution can be prepared." In this way, the device can function as a drug-delivery mechanism. "In effect, release is modulated to give the right amount (dosage) of insulin at the correct time. Insulin would be loaded into the device by equilibrium partitioning," according to the researcher.

Byrne adds, "With this device we would expect good bioavailability of insulin. As far as the in vivo placement of the device or gel system, many factors become important, such as ease of placement in terms of surgical procedure, and the area of body where there is representative sample of true blood glucose levels."

Although the application is a few years in the future, Byrne says "we are analyzing current IDDM [insulin-dependent diabetes mellitus] treatment methods (e.g., islet cell transplantation sites) and will design and optimize our system to achieve low immunogenicity, no toxicity, good insulin bioavailability and release kinetics, and so on."

Clay Reduces Permeability of Medical Polymers

A team of researchers from Penn State University (University Park, PA) are using a compound commonly found in cosmetics and antacids to make polymer parts in artificial heart devices less permeable to air and water. The polymers used for various parts of artificial heart devices can be penetrated to some extent by air or water. Says James Runt, PhD, professor of polymer science, "We decided to look at two methods for decreasing permeability—a chemical method and a nanocomposites approach."

The researchers explain that the chemical method entailed use of a polymer similar to that already used for the pumping chamber, cannula, and compliance chamber in a left ventricular device developed by Arrow International (Reading, PA) and Penn State, and in earlier heart devices. In the current devices, air inside the compliance chamber helps in the pumping. Over time, however, air seeps through the polymer wall of the chamber into the body and dissipates. This requires the air to be replaced periodically. The polymer is also permeable to water, and additional care is required to ensure that the electronics in the devices remain dry.

Polyisobutylene chains are attached to a standard polymer to form a comblike structure, which functions as a barrier for air and water.

The researchers report that they took the standard polymer and attached polyisobutylene chains to it to form a comblike structure. The hope was that these structures would create a barrier for air and water. Up to 35% by volume of polyisobutylene was incorporated into the poly (urethane urea) material. The resulting polymer had good mechanical properties, but has not been tested for fatigue resistance, according to the research team.

The alternative solution to the problem was based on use of a commercially available silicate clay, Cloisite 15A, produced by Southern Clay Products. The material is an alkyl ammonium–modified montmorillonite. The researchers explain that when the constituent silica layers are mixed with the polymer in a common solvent, they disperse throughout the solvent. When the solvent is removed, the layers remain distributed to some extent.

"With an addition of 20% by weight of this modified silicate, we achieved a decrease in permeability of a factor of five," Runt explains. "This method is much more convenient than the chemical method and produces a far greater decrease in permeability."

Says Runt, "The chemical approach we took was relatively complex and resulted in about a factor of two reduction in permeability to water vapor and oxygen. Not bad, but not as low as we were looking for. Nanocomposites of rubbers and plastics with layered silicates are being investigated in both the industrial and academic sectors, and I felt that there was a natural extension to the biomaterials sector."

Runt says the initial research was done on nonoptimized compositions and preparation methods. "There is real work to be done in optimizing these, and hopefully improving performance even more. Also, biocompatibility and flex fatigue for materials that are being considered for blood pumps are still open issues."

Kidney Lives in Machine Simulating Human Body

Researchers at the University of Chicago Hospitals are developing an organ preservation method that could help improve transplantation procedures. Currently solid organs removed from donors must be placed on ice and maintained at 4ºC until they can be transplanted. Cooling the organs slows cellular activity and reduces metabolic function. However, exposure to cold can damage the organs and they must be used quickly to minimize such effects. In addition, as an organ is reperfused with warm blood, it often sustains further damage.

Using the new technique, the university researchers report, a kidney has been preserved—functioning in the same manner it did in the donor's body—for almost 24 hours without exposing the organ to cold. The machine, called the Portable Organ Preservation System (POPS) is being developed to enable organs to be kept in a warm, blood-based, oxygenated, nutrient solution.

"This could transform the way transplants are performed," says David Cronin, MD, assistant professor of surgery at the University of Chicago. "POPS could make it possible to keep organs undamaged for much longer periods of time. We would have more time to properly prepare both the patient and the organ for transplant surgery," he adds. Cronin and a team of university researchers are working with TransMedics (Woburn, MA) to develop the device.

The POPS device is intended for use with all organs that are currently used in transplantation procedures, including kidneys, lungs, and hearts. Cronin has been involved in the design of the POPS for the past three years. According to the researcher, more than 500 animal organs, including hearts, kidneys, and livers, have been tested on the machine in the last 18 months.

The first human organ storage in the POPS was reported on August 25, when the researchers removed a human kidney from the machine at the end of 24 hours. Data on the functioning of the kidney while it was in the POPS are being analyzed, and the group is examining the kidney itself in detail to see how it was affected.

The organ appears to have behaved exactly like a kidney in a human body. As blood is pumped through it in a way that mimics the heart's pumping, the blood was filtered and the kidney made urine normally. Animal organs that have been tested have all behaved normally.

"We are currently forced to maintain a very high bar for organs used in transplant," says Cronin. "A patient receiving a heart or liver that doesn't function may not get a second chance. This system, in addition to giving us time, allows us to see that the organ is functioning and perhaps even repair it. This technology could expand the range of usable organs and save lives." Cronin explains that the POPS could conceivably be used to help "weed out" organs that are unfit for transplant.

Real-Time Detection of Ions and Biomolecules

A sensitive and flexible molecular sensing system that detects a broad array of analytes from small ions to nucleic acids to proteins could have a significant impact on pharmaceutical research and clinical diagnostics. The system is being developed by Charles Lieber, PhD, and Hongkun Park, PhD, who are the cofounders of Nanosys Inc. (Cambridge, MA) and professors at Harvard University (Cambridge, MA).

The researchers explain that the sensor uses a nanowire—one ten-thousandth the width of a human hair—to which specific capture molecules have been affixed. These molecules detect the presence of minute quantities of analytes, such as ions, nucleic acids, and proteins.

Detection is performed using inexpensive and portable low-voltage measurement equipment. This eliminates the need for cumbersome and expensive chemical labels, such as fluorescent dyes, and sophisticated optical equipment, such as lasers, according to the researchers.

There are a number of potential advantages that the new technology may make possible. According to Lieber, "The unique features of the nanosensor could reduce the cost of existing types of detection tasks, but more exciting to us is the ability to do things simply not possible with other technology."

Lieber explains that the nanosensor could be used to carry out DNA detection without amplification. "This has been somewhat of a holy grail and enables direct analysis of genomic DNA samples," he says, adding that this would be useful in large-scale disease association studies. "Of course, this type of analysis could be carried out in an array format, but the key is doing so without the need for PCR [polymeric chain reaction] amplification or costly organic labels."

Lieber also says the nanosensor could be used to perform single-cell analysis of large numbers of species—both on a given cell and on each cell in an array. It could also simultaneously monitor expression levels of a large number of nucleic acids and proteins in real time and study the influence of exogenous species, such as potential drugs, on these species. "This could be useful in understanding pathways involved in disease as well as for evaluating therapeutics," he says.

The technology could also provide powerful diagnostics. "In an integrated, cheap package, one could have a home test for a suite of cancer markers in the same way that a glucose test is done by diabetics," Lieber says. "Being able to make such measurements with regularity. . . with a minimally invasive real-time device would enable cancer detection at its earliest stages when it is most treatable."

Lieber further notes that "the same type of technology can be implemented in cancer marker discovery. So this sensor readily lends itself to basic biology research and subsequent transition to diagnostic [applications]."

Copyright ©2001 Medical Device & Diagnostic Industry

Bush Taming FDA? Some Think Not

Originally Published MDDI October 2001

WASHINGTON WRAP-UP

The appointment of a conservative chief counsel at FDA has industry wondering if it is the first in a series of moves designed to establish an attitude of less-rigorous enforcement at the agency.

James G. Dickinson

FDA Policy on SUDs Called 'Irrational | Industry Faults FDA Efforts to Ease Regulation | FDA Rejects TMJ Implants Protest | Heart Valve Took 15 Years to Approve

Washington circles that watch FDA closely have been rife with rumors about the Bush administration's plans for the agency. The longer FDA goes without a commissioner, the more the pressure to fill the vacancy grows, fueled by industry complaints that without a leader bureaucrats are becoming more unreasonable.

Along with more-frequent plant inspections and slower progress on "least burdensome" paperwork reforms, there have been episodes that some FDA-watchers characterize as device-review abuses. These include the TMJ Implants case, covered previously in this column, which has now moved into the political arena, and the even slower FDA approval of the MedicalCV Omnicarbon heart valve. (Both issues are covered below.)

These situations are extremes, of course, and most companies have fared better. But these examples add to the political static in Washington, and to expectations that new Bush appointees will "rein in" FDA. The biotech industry is even more impatient on this issue than the device industry.

In August, no strong front-runner had yet emerged in the quest for a commissioner. But the administration let go FDA's chief counsel of 11 years, Margaret Porter (appointed in the first Bush administration). Taking her place was conservative lawyer Daniel E. Troy, of the Washington law firm of Wiley Rein & Fielding. A former clerk of controversial conservative judge Robert Bork and a scholar at the conservative American Enterprise Institute, Troy has written strongly in favor of full constitutional protection for commercial speech in advertising. Such protection could stifle FDA and FTC regulation of promotional materials.

At first, Troy's appointment was seen as a move to curb FDA's excesses, crafted to get around Democratic opposition in the Senate to the likely nomination for commissioner. Earlier rumors that President Bush intended to nominate one of a clutch of industry-connected conservatives had provoked liberal senator Edward M. Kennedy and his allies on the committee that will confirm any new commissioner to protest in writing to President Bush.

Thus, Troy's appointment—which needed no advice and consent from the Senate—was seen as a reaction to that protest. Until Bush is able to place someone in the commissioner's office who will meet Kennedy's approval, perhaps Troy can bring about more regulatory circumspection at the agency.

In a brief statement to this writer, Kennedy said Troy was known to be "a staunch opponent of efforts to have vigorous FDA enforcement." Because this selection does not require Senate confirmation, he added, "there is nothing we can do about this." Kennedy said he disagrees with Republicans who think FDA is an agency that needs reduction.

A similar criticism came from Public Citizen Health Research Group director Sidney M. Wolfe. The Bush administration chose Troy, he said, "because they want to get in someone who represents the business interests, someone who believes that commercial free speech has got to be left so free that you can't come down on advertising." Wolfe said he had let it be known inside FDA's Office of Chief Counsel that he wants to be told if Troy "does things that are several standard deviations off of what they should be doing. If this person is not going to facilitate law enforcement, or is going to block it, then he needs to be pushed out as quickly as possible."

Such views of Troy were quickly counterbalanced by positive assessments, however. Peter Barton Hutt, dean of FDA lawyers, spoke enthusiastically of the appointment. "He's a superb lawyer, [he] comes with breadth of experience, he's a hands-on person. He reminds me a great deal of where I was when I came to the agency."

"When I came to FDA," Hutt said, "everybody predicted I was there as a token for the industry, and I think that was disproved pretty quickly. [Troy] wants to help the agency, he wants to work with the agency, he wants to learn a lot about it, and he wants to do a damn good job, like any good lawyer would want. I'm very enthused." Hutt said he had spent "quite a bit of time" with Troy discussing the position since his appointment became known. Troy, he said, is "going around town and meeting with all kinds of people" to learn about the job.

As for Troy's outspoken views on the First Amendment and criticism of FDA's attempts to restrict manufacturer support of educational and scientific materials, Hutt said: "He's right. FDA has had its head in the sand. They've lost every single court decision on this. They are destroying their credibility in the courts. You can't just pretend that the First Amendment doesn't exist—that's ludicrous. As long as FDA tries that, they aren't going to win a single court case, and they're going to have everybody in the country litigating against them."

Hutt predicted that Troy will be sympathetic to strong FDA enforcement. Noting that this was just as he himself had always been, Hutt took the opportunity to lambaste Congress for "strangling FDA to death."

Two other former FDA chief counsels, Tom Scarlett (Reagan administration) and Nancy Buc (Carter), also expressed optimism about the appointment.

Scarlett said he expected that Troy "is probably going to be a good chief counsel." He agreed with Troy's criticisms of FDA's "uphill climb" in arguing against the Washington Legal Foundation.

Although coming from the opposite side of the political spectrum, Buc warmly applauded the choice, saying Troy "is a terrific lawyer."


FDA Policy on SUDs Called 'Irrational'

CDRH's policy on single-use devices (SUDs) is irrational, unlawful, and in the absence of adequate safety and effectiveness data, fails to protect patients, asserts the Association of Disposable Device Manufacturers (ADDM) in an August 3 citizen petition. The group is requesting that FDA regulate SUDs as reusable medical products. In addition, the agency should refuse to approve PMAs or 510(k)s for reprocessed SUDs that are labeled "single use only," ADDM claims.

The petition says that giving premarket approval to multiple-use devices labeled as single-use is both false and unlawful because the conditions of use stated in the product's labeling are not those under which the devices are intended to be used. In fact, the group says, since these devices are not shown to be equivalent to other multiple-use devices, they are actually unapproved Class III devices, and therefore adulterated under FDA's own standards.

ADDM's petition faults FDA's premarket guidance and other agency correspondence that allow a reprocessor to label a reprocessed SUD "single use only" even when the device has not only been previously used, but will be reprocessed again after the current use. "The practical effect of this policy is that, unlike submissions for all other reusable devices, reprocessors' premarket submissions will not contain data demonstrating that the device is safe and effective after multiple reprocessing procedures, or data establishing the maximum number of reuses for a given device."


Industry Faults FDA Efforts to Ease Regulation

An FDA draft guidance on the least burdensome ways of regulating medical devices must be aggressively implemented or the benefits of the principles in the document will not be realized, says industry association Adva-Med. The group's comments came in a July 30 response letter to a draft FDA document, "The Least Burdensome Provisions of the FDA Modernization Act of 1997: Concept and Principles." The association said that if these principles were "applied within the spirit in which they were written, then a productive collaboration between FDA and industry representatives could result."

AdvaMed's letter said it approves of the agency's interpretation of the least burdensome concept and the scope of its application to all medical devices, including in vitro diagnostics and all pre- and postmarket activities. However, the group stressed the need for training and follow-up activities within the agency. "The least burdensome concept represents a cultural shift within FDA and this shift will occur only through effective training activities conducted at periodic intervals with appropriate follow-up and reinforcement," the group said.

Similarly, AdvaMed recently told FDA in a June 26 letter that its requirements for hepatitis C assay PMAs as outlined in a new guidance document are excessive, considering that these products have been marketed without significant problems for some time. The object of AdvaMed's remarks was the document, "Guidance on Premarket Approval Applications for Assays Pertaining to Hepatitis C Viruses (HCV) That Are Indicated for Diagnosis or Monitoring of HCV Infection or Associated Disease." It should be revised to allow the use of well-characterized stored samples to demonstrate the safety and effectiveness of these products, the group said. "We believe that this concept for sample bank correlation studies should be added to the next draft of the guidance, with the stipulation that each stored sample have sufficient patient clinical information so that the patient information can be used for discrepant resolution when the tests being compared do not give the same answer."

The group complained that the guidance was overly burdensome. For example, the document recommends that many studies be performed in each matrix to be claimed (serum and each plasma type). "This should only be necessary if differences in performance are demonstrated during serum/plasma equivalence studies," Advamed said. "Where equivalent performance has been demonstrated, it would be overly burdensome and unnecessary to perform stability, analytical sensitivity, interference, reproducibility, etc., on each matrix type."


FDA Rejects TMJ Implants' Protest

Relationships that the lead reviewer of TMJ Implants Inc.'s devices had with a variety of individuals and entities during the review "do not constitute a violation of the 'conflict of interest' criminal statutes or regulations." So wrote FDA Office of Internal Affairs special agent in charge Donald L. Briggs, Jr., in a July 25 letter to company president Robert W. Christensen. He was replying to complaints Christensen had made about the reviewer, Susan Runner, and her prior relationships with a consultant to a trade competitor, two FDA advisory panel members, a temporomandibular joint (TMJ) patients' support group, and FDA's Office of Women's Health.

Christensen had contended that Runner's relationships with these entities were evidence of bias against his two pre-1976 prostheses, which FDA had forced from the market for 20 months pending a problem-plagued review of their PMA applications. The devices were ultimately approved last February.

In his letter to Christensen, Briggs said his office "is declining to investigate these matters. However, since your letter indicates you are seeking an HHS Office of Inspector General investigation, I am forwarding your letters, with attachments, to the HHS Office of Inspector General, via this letter, for any action they deem appropriate."

However, like Briggs's office, the Inspector General's office has declined to investigate Christensen's complaints, except in the context of a broad examination of CDRH device-review practices.

Briggs's letter crossed in the mail a letter Christensen faxed to CDRH integrity officer Carl De Marco. In it he criticized both De Marco and CDRH ombudsman Les Weinstein for claiming an inability to investigate allegations of wrongdoing by FDA employees. By taking this stance, he said, the two "have become deflection officers whose functions appear to have been to protect the bureaucracy, including perhaps supervisors who failed to address employee misbehavior when evidence of that behavior is so strong."

Christensen wrote that FDA has "a history of cover-up," not only in his case but also in a 1995 case involving the Tukwila, WA, dental monitors manufacturer Myotronics, which was investigated by a House subcommittee. In that case, Christensen told De Marco, "chairman Joe Barton (R–Texas) made it abundantly clear that the [Office of Internal Affairs] did not have the ability to investigate FDA wrongdoing and thus referred it to the IG. . . . If you are sincere in your desire to see the TMJ Implants Inc. case objectively investigated, you will assist the company in its efforts to compel both congressional hearings and an IG investigation."

Christensen copied his letter to 17 senators and representatives, including Barton.


Heart Valve Took 15 Years to Approve

FDA moved too slowly to approve a heart valve device that could have saved thousands of lives, the Competitive Enterprise Institute (CEI) complained in a July 27 statement. The statement coincided with the device's approval after a 15-year review. The conservative think tank said MedicalCV's Omnicarbon heart valve has been available on the European and Japanese markets since 1986.

According to CEI, Medical Incorporated, now MedicalCV, filed its PMA application in 1986. FDA denied it in 1989, however, requesting more information from the company. "Ironically," says the Institute, the device was developed in the United States, and "for at least 15 years has been manufactured here and exported with FDA approval. Only now, however, will it actually be available to physicians and patients in this country."

"The Omnicarbon's pyrolite construction significantly reduces embolism risk," said CEI. Citing the statistic that approximately 16,000 heart valve recipients a year die from bleeding complications in the United States, the group argued that the Omnicarbon valve offers major life-saving benefits. These benefits were denied to the American public due to FDA's 15-year delay, said CEI.

According to MedicalCV, the now-approved device is a monoleaflet (tilting-disk) mechanical valve, with both the disk and the housing ring constructed from pyrolytic carbon. It is rotatable, causes minimal cardiac energy loss, and has a particularly low complication rate for both thromboembolism and hemorrhage, the company said.

CDRH Office of Device Evaluation deputy director for clinical policy Dan Schultz described the Omnicarbon review as an "aberrant" case that involved an "excessive amount of time." Not many people in the center remember the early difficulties that faced the PMA application when it was submitted, but they do recall that the aftershocks of the Shiley heart valve failures were still affecting the reviews of all heart valves. "There was an attitude of relative conservatism," Schultz said.

In addition, there were scientific disagreements about the clinical data submitted by the sponsor. As time passed, interpretation of the data became increasingly difficult in light of changes in medical practice and the design of clinical protocols. "If you don't get an early approval, and the review extends to 3, 4, or even 5 years, these difficulties become greater," Schultz said. There were also periods when the company "was not terribly responsive" to reviewers' concerns.

Finally, the review took so long that, paradoxically, those disagreements about the data were gradually overtaken by accumulated clinical evidence from the trials. This event finally enabled the center to approve the device despite those data-oriented concerns.

James G. Dickinson is a veteran reporter on regulatory affairs in the medical device industry.

Copyright © 2001 Medical Device & Diagnostic Industry

Looking Toward A New Medical Technology Policy

Originally Published MDDI October 2001

FIRST PERSON

The emergence of new medical technologies requires FDA reform, liability relief, and a reassessment of current policies on third-party reimbursement.

Joshua A. Adler

Earlier this summer, a man in Kentucky received the first self-contained artificial heart, and Vice President Cheney had a pacemaker implanted in his chest. The artificial heart, now in its first human test, is a breakthrough for science. The pacemaker, already implanted in thousands, has been a commercial breakthrough for Medtronic.

Which kind of breakthrough—the scientific or the commercial—is more remarkable? For small companies that lack Medtronic's resources it may be the latter, for the barriers to bringing innovations to the public can seem insurmountable.

A more sensible regime than the patchwork we suffer from today would produce substantial benefits for America's physiological and economic health.

A comprehensive policy should cover at least FDA reform, liability relief, and third-party reimbursement.

FDA REFORM

For an entrepreneur, FDA can be daunting. Fears of arbitrary regulatory delays deter all but the most intrepid prospective investors, raising the cost of capital for new research and development efforts. Small companies must hire consultants and lawyers to deal with FDA, which diverts resources away from innovation.

A move toward a regulatory strategy based on the European system would alleviate these problems. It is difficult to overstate how much more efficient their system is compared with ours. That is why many new medical technologies are available to European consumers many years before they reach the United States. For example, one of my company's products took a year to clear in Europe—a year of preparation, and a three-day inspection. The identical product in the United States required about three years of preparation and a year of government review.

Perhaps such delays are necessary evils of regulation. But a larger trend threatens to make FDA obsolete. The proliferation of health applications for the Internet and digital devices is blurring the line between medical and nonmedical technology. When a heart monitor can "talk" with a patient's cellular phone—which can then automatically call emergency services—will FDA need to regulate all phones, global positioning systems, and telecommunications? When diabetics' palm PCs can scan glucose level and update on-line medical records, will FDA inspect Compaq, IBM, and any Internet intermediaries? Under its current charter, it must.

LIABILITY RELIEF

If a new healthcare technology saves 99 lives that otherwise would have been lost, but fails for one person whose condition might have been hopeless, the perception in the medical industry today is that the one failure will void the 99 successes. No technology can be perfect, and each .9 added to a 99% success rate raises manufacturing costs tenfold, making the affected products unaffordable to the people who need them most.

Fear of liability, even when a company has made its best efforts to produce a quality product, adds incalculable financial risk to new ventures. It also stifles the kind of risk-taking that leads to advances.

THIRD-PARTY REIMBURSEMENT

Third-party reimbursement is essential for a successful new medical product. Figuring out the coverage requirements for Medicare, 50 Medicaid agencies, and hundreds of private payers can overwhelm many small organizations. The process tilts investment decisions away from the most original new ideas toward product categories that already have established coverage. For the most part, the return on a new medical-technology investment can only be as good as the reimbursement rate. Thus higher costs for market entry do not necessarily translate into higher returns—contrary to economists' ideals.

Reimbursement by Medicare, the largest healthcare payer in the world, makes or breaks many new medical products. Private healthcare payers often follow Medicare's lead. The Centers for Medicare and Medicaid Services (CMS) can be assumed to base decisions on utilitarian principles to ensure the greatest good for the greatest number. But the law governing Medicare has not changed since 1965— despite enormous changes in the healthcare environment. Even the most fundamental aspects of Medicare—such as the divide between Part A and Part B reimbursement—make little sense today.

Healthcare is a continuum, and smart spending on prevention or early intervention can save money on hospital visits down the line. But Medicare is not permitted to use cost-effectiveness as a basis for decisions, and cannot pay for preventive medicine in most cases. Without new thinking, our aging demographics will sink Medicare in the next decade.

President Bush has already demonstrated a degree of commitment to the life sciences by fully funding the National Institutes of Health, a cause that draws bipartisan support. The reforms outlined above would maximize the return on those investments, stimulate our economy, and provide the basis for accelerating growth in the coming decades.

Joshua A. Adler is vice president of business development at iLife Systems Inc. (Dallas, TX).

Copyright ©2001 Medical Device & Diagnostic Industry

Developing A Fingertip-Sized Implantable Heart Pump

Originally Published MDDI October 2001

COMPUTER-AIDED DESIGN

At the École Polytechnique de Montréal, associate professor André Garon and other researchers have designed a tiny pump capable of being inserted directly into a cardiac patient's heart. The auxiliary pump, said to be the smallest of its kind in the world, is only 22 mm in diameter—about the size of a fingertip. While not intended to replace a heart, it will be inserted directly into the left ventricle of damaged hearts to serve as a temporary bridge to transplant and to prolong the life expectancy of children with congenital heart defects. Eventually a more permanent implant could be achieved, for up to 10 years or more. In addition, the device could be removed when a damaged heart heals and can function on its own.

The design and solid modeling of the pump was done by Garon using CATIA software. CATIA was also used to produce the numerical control commands that allowed the lab to machine prototypes of the very small parts that make up each pump. High-speed, five-axis tools were used to form precision titanium blades that are only 100 mm thick and rotate at 1–12 rpm.

Cardionove's implantable heart pump is only 22 mm in diameter.

Garon, who also teaches CATIA, is president of Cardianove Inc., which was formed to oversee the eventual production of the heart pump. The project was conceived at the Montreal Heart Institute, where a small pump was needed to assist failing hearts.

According to Conrad Pelletier, MD, Cardionove CEO, the device is likely to prove useful as more than just a bridge to transplant. "It's probably going to be the first application, but there will be other applications besides that one. One of the other applications we foresee is a bridge to recovery." Pelletier explains that "some of the acute illnesses of the heart can recover if sufficient time is allowed. And very often, these patients are so sick that they have to undergo transplantation if we want them to survive. Now if we could supplement or support the heart for awhile, it's possible that some hearts might recover completely. Then the device could be removed and the patient recover completely. So that would be another application. And the last one, which is a long-term application, would be a definitive implant. This would be for patients who have chronic heart failure but who, for any reason, can't go through heart transplantation, either because of an insufficient number of donors, or because they have a specific contraindication to heart transplantation. And we could probably use this device as a permanent implant."

Pelletier says the new pump provides a number of advantages when compared with conventional technologies. "The first one is improved efficiency of performance," he says. "We are looking at performance in the range of 40% to 50%, as compared to roughly 25% with current devices." He explains that a more efficiently performing pump requires less energy for activation. "Thus the energy source will last longer, with longer periods of autonomy for the patient, when he can rely exclusively upon his internal battery." He adds, "The second one is the miniaturization of our model. The actual size of the pump that we are developing is close to half the size of existing pumps. So we are looking for a pump that will probably be the only one that could be implanted inside the heart rather than in parallel to the heart."

Says Pelletier, "The major advantages interior implantation presents are that you avoid damage to the heart muscle from the pump inflow and there is no need for sutures to vessel walls for outflow from the pump. It will be inserted within the left ventricle and have the inflow directly from the left ventricle and the outflow directly into the aorta without any sutures or damage to the myocardium, contrary to existing pumps."

Pelletier explains that the device is powered by a conventional battery system. Describing the system, he says "it will work basically with two sets of batteries. One will be internal, giving the patient the opportunity for total autonomy for up to one hour daily. For instance, to take a bath or a shower, or to go swimming, for that matter. And the other set will be an external battery that will support the patient throughout the remainder of the day. The external battery will also act as a recharge source for the internal battery."

Copyright ©2001 Medical Device & Diagnostic Industry

Answering the Call for Harmonization of Medical Device Alarms

Originally Published MDDI October 2001

ALARMS

Industry sounds off on a new document aimed at standardizing the design of alarm systems for use in medical equipment.

Michael E. Wiklund and Eric A. Smith

To many medical device manufacturers, the notion of a medical device alarm standard is, well. . . alarming. That the draft of a standard jointly developed by the International Electrotechnical Commission (IEC) and ISO has grown to more than 60 pages in length is more alarming still. After all, one might ask, shouldn't alarms be simple? Is there really that much to say about designing an effective alarm system? Couldn't the basics be covered in just a few pages, and the rest be left to the designers?

Designing an effective alarm system is not so simple, though the end result should be. For starters, there are numerous design options to consider, such as auditory alarms, visual alarms, and combinations of the two ( e.g., a flashing light accompanied by a beep). One can even annunciate a warning with a tactile cue, similar to the way a pager vibrates to draw attention in a noisy environment or to avoid distracting others.

To complicate matters further, designers must consider the varying degrees of alarm required to alert users to conditions ranging from minor concerns to deadly threats. There are alarms that signal active problems, such as a dangerous arrhythmia, and those that indicate such a problem has occurred and has already righted itself.

When one factors in the wide variety of medical devices currently in use and the needs of a multidisciplinary, multicultural, global user population, the development of a standard of any length seems like quite an accomplishment.

The emergence of an alarm standard draft reflects the medical device industry's overall desire for harmonization, fueled by anxiety about clinical mishaps. One could draw an analogy to the standardization of traffic signals and road signs: Americans are well served by the red, yellow, and green traffic-light convention, as well as the common stop and yield signs. If these visual cues varied from one state to another, one city to another, or even one intersection to another, chaos and more traffic accidents would likely ensue.

Just as harmonization makes drivers' lives easier, so should harmonized alarms make medical workers' lives easier. And, in contrast to the variation in the style of traffic lights and signage from nation to nation, the harmonization of alarms will be global, theoretically enabling manufacturers to develop one alarm system for all markets.

Again, the standard under development is an initiative of ISO and IEC. The document, which is expected to constitute the eighth collateral standard to IEC 60601-1: Medical Electrical Equipment—Part 1: General Requirements for Safety, is titled "General Requirements and Guidelines for the Application of Alarms in Medical Electrical Equipment." A joint working group of ISO Technical Committee 121, Subcommittee 3, and IEC Technical Committee 62, Subcommittee 62A, began work on the collateral standard in 1997. Current plans call for the final standard's release in another year or so.

The group's second working draft, circulated in December 2000, generated an unusually large number of comments from the medical device development community. Many of the comments were highly critical of the first-of-its-kind standard, and, in some cases, indicated the need for major reorganization. The group met for a third time in Vancouver this past July, and again this September in Andover, MA, to continue working toward a revised draft for public comment. At press time, the next meeting was scheduled for March of next year, in London.

THE NEED FOR STANDARDIZATION

The need for an alarm-system standard is strong. A general inconsistency among devices, coupled with the human-factors shortcomings of some alarm systems, presents major headaches for users. The draft standard's introduction highlights these problems, stating, "Surveys of healthcare personnel have indicated widespread discontent with alarm signals. Problems include difficulty in identifying the source of the alarm signal, loud and distracting alarm signals, and high incidences of false-positive or -negative alarm conditions. . . Often, alarm signals are more confusing than enlightening. Many operators respond to alarm signals by disabling the alarm system or by adjusting a[n] alarm limit to a[n] extreme value that effectively disables the alarm system."

Currently, medical workers must learn the characteristics of each medical device's alarm and be able to differentiate between them. For example, one device may announce an alarm condition with a rapidly flashing red light and a repeating beep, while another might emit a steady amber light accompanied by a set of ascending tones. Workers may also struggle to understand the nuances of the more sophisticated alarm systems. The distinctions between "alarm silenced," "audio inhibited," and "audio suspended," for example, are difficult to discern.

Alarm-system design shortcomings are more than a mere nuisance. Inadequacies can lead directly or indirectly to patient injury and death, as can habits developed by workers to avoid the distraction of false alarms, such as turning the alarm system off entirely. While making alarm systems better may not head the list of remedial actions taken to save lives, it certainly stands to make a positive difference.

DETAILS OF THE STANDARD

The alarm design standard evolved in part from guidance provided in three existing ISO documents: ISO 9703: Anaesthesia and Respiratory Care Alarm Signals—Part 1:1992: Visual Alarm Signals, Part 2:1994: Auditory Alarm Signals, and Part 3:1998: Guidance on Application of Alarms. It covers a wide range of alarm-system design characteristics, including:

  • Activation states.
  • Prioritization.
  • Annunciation.
  • Auditory signaling.
  • Visual signaling.
  • Remote signaling.
  • Limit setting.
  • Alarm resetting.
  • Data logging.

Portions of the draft standard are quite detailed, leaving little to designer discretion. For example, one particular part of the document states that alarm systems should include at least four auditory alarm-signal harmonic components within the range of 300 to 4000 Hz. It recommends that a high-priority alarm indicator light be red and flash at a frequency of 1.4 to 2.8 Hz, with a duty cycle of 20 to 60%. Other parts of the standard are more open to interpretation in that they establish basic requirements but leave the details up to the designers.

INDUSTRY REACTION

The large number of comments on the draft standard was not surprising, considering the significant impact the standard will have on medical device design practices. Manufacturers spend considerable time and money developing and validating their proprietary alarm systems, some as brand-specific as the company's logo. As a result, device companies are naturally protective of their approaches to alarm design and what they perceive to be good for customers and for gaining a competitive advantage.

Carl Pantiskas, a clinical engineer at Spacelabs Medical (Redmond, WA) who has reviewed and commented on the draft standard, concurs. He states, "Spacelabs Medical has put a lot of thought into the design of alarm systems for [its] patient monitors. I would expect any organization that has a good solution—one that has been validated through years of effective clinical use—to be somewhat reluctant to change it to something that may not have gone through the same rigorous validation. You'd have to question whether [the standard was] actually improving things." That said, Pantiskas acknowledges the overarching value of alarm-system harmonization, adding, "I fundamentally believe that an alarm standard is necessary, just as long as the standard is realistic and does not restrict technological innovation."

Pantiskas's specific concern is that the draft as it is currently written does not fully account for the entire range of medical device use scenarios, including the use of devices in the home, and the technological options available to alarm designers. He points out, for example, that the standard should take into consideration the needs of the hearing impaired. He also anticipates that new technologies and applications, such as those found in telemedicine, may introduce alarm-system design issues that transcend the device-focused guidance in the standard. Moreover, Pantiskas worries that the guidance might not be relevant to networked devices or devices warranting advanced alarm-system designs.

Pantiskas's concerns match several others in the body of comments on the standard, so those responsible for the draft—who may feel that the standard already addresses a wide variety of use scenarios—will need to reopen their discussion. Such deliberation is representative of the nature of any collaborative effort to develop and refine a common standard. The creative tension between professionals with differing and sincere viewpoints ensures that the final standard will reflect myriad compromises but will ultimately be good for the industry.

KEY ISSUES

Patterns emerge within the voluminous comments on the draft standard. Some reviewers find the document complex and hard to follow, which suggests the need for extensive reformatting. Some argue that the alarm-system requirements are laden with overly specific design recommendations. Others see the draft stand-ard as being too focused on medical equipment that is closely attended—devices used in the operating room, for example—at the expense of equipment that is typically attended less vigilantly, like that used in acute-care settings. Still others are concerned with the standard's attention to usability design characteristics considered by some to be unrelated to patient safety. A few believe that the standard is better suited to the characteristics of complex devices than those of simpler ones. Another criticism is that the drafters of the document try too hard to "teach" readers about the human-factors engineering of alarm systems.

Within the committee itself, there reportedly is considerable debate on the value of adding an informative annex to the standard that prescribes a set of eight alarm sounds. The idea behind the appendix is that alarm conditions associated with medical devices can be divided into logical categories, each with its own unique alarm sound. The categories, as outlined in the appendix, are:

  • General.
  • Cardiac.
  • Perfusion.
  • Ventilation.
  • Oxygen.
  • Temperature/energy.
  • Drug or fluid.
  • Equipment or supply failure.

As such, a ventilator alarm would sound different than an infusion pump alarm, and a clinician would know instinctively where to look, once the disparate sounds become familiar.

In the appendix, each category is assigned a series of musical notes (a, b, c, d, e, f, and g) designed to be easily distinguishable from one another. High- and medium-priority alarms would be annunciated by a series of five and three notes, respectively.

A high-priority cardiac alarm, for instance, would be annunciated by the series: c, e, g, g, C (the small c and large C denote the same note, one octave apart). The alarm-sound designers intend users to map the syllables of the phrase cardiac alarm to the notes. Accordingly, the mapping would be as follows: c = car; e = di; g = ac; g = a; C = larm. The overall sound would be comparable to a trumpet call or the National Broadcasting Company's familiar television chime.

Whether this kind of mapping will produce real benefits, particularly among medical workers who do not speak English, is uncertain. Yet it seems reasonable to assume that the operators of the equipment would come to associate tones with their appropriate equipment type.

Stephen Dain, MD, a practicing anesthesiologist at the London Health Sciences Centre (London, ON, Canada) who has contributed substantially to the draft standard, firmly believes in the syllable-mapping approach to annunciating an audible warning. But he acknowledges another significant concern about the eight-tone concept, one that has caused intense committee debate about the appendix and could ultimately lead to its exclusion from the standard. Dain states, "The recommended sounds have not been sufficiently validated. We don't know for sure if they are the best possible tones or whether or not users will be able to differentiate between them and correctly associate them with specific equipment. We need to do the user research. But, if we don't take this approach, alarm systems will share the exact same tones, making it more difficult to isolate a particular alarm."

Figure 1. A sampling of recommended alarm symbols.

Similar concerns persist regarding a set of recommended alarm symbols, such as those shown in Figure 1. When the authors of the draft standard conducted an industry-funded study of potential device users to determine the symbols' reliability, they found that many clinicians experienced difficulty understanding and differentiating the symbols—a finding that was passed along to the technical committee. The study underscored the importance of validation testing as a prelude to standardization.

COMPLIANCE

When IEC releases the final standard, it might be incorporated directly into the third edition of IEC 60601. More likely, it will be issued as a collateral standard to the second edition of IEC 60601. Either way, the final document will wield the power of a voluntary standard that reflects the industry's consensus on best practices. It will not have the power of government regulations, and, as such, manufacturers will not necessarily be required to comply with it. Rather, manufacturers can continue developing products that incorporate proprietary alarm systems, but they will do so at their own risk. One such risk for a device manufacturer is becoming the target of a product liability claim that points to a noncompliant alarm system as the cause of injury. There is also the risk that customers will gravitate toward compliant devices—and away from noncompliant ones—to establish alarm-system consistency within their institutions.

According to common practice, existing medical devices would likely be grandfathered, meaning their alarm systems would not be subject to the new standard. The principle of grandfathering is somewhat complicated, however, by the fact that alarm-system behavior is often controlled by software, a device component that is updated over time. This means that some existing medical devices could be updated to comply with the new standard. Thus, one can expect some manufacturers to make the updates to existing medical devices, if only to maintain product-line consistency.

Interestingly, the draft standard permits manufacturers to replace the recommended alarm sounds with any number of alternative sounds. The only stipulation is that the alternative sounds be validated; however, the committee has yet to validate even the recommended sounds.

CONCLUSION

Clearly, the alarm-system standard needs further refinement before it is ready for public release. According to industry reviewers, it must be made easier to use, it must focus more on general alarm characteristics than on integrated solutions, and it must apply to a broader range of devices. In addition, its recommendations need to be validated through user testing.

When they are complete, however, the guidelines set forth in the standard will be valuable to medical device designers, manufacturers, clinicians, and patients alike. Designers will have set guidelines to follow in developing application-appropriate alarm systems, which in turn will save manufacturers time and money. Clinicians will benefit from alarms that are more informative, enabling them to perform better and enhancing patient care.

Copyright ©2001 Medical Device & Diagnostic Industry

President's 2002 Budget Request Continues Commitment to NIH

Originally Published MDDI October 2001

R&D DIGEST

Since fiscal year 1999, the National Institutes of Health (NIH) has benefited from growing public support, as well as the ongoing commitment of the legislative and executive branches of government.

According to Ruth Kirschstein, acting director of the NIH, additional funding that has been appropriated "progress in medical sciences is advancing at a speed we only dreamed of a few years ago." Commenting on President Bush's fiscal year 2002 budget request, Kirschstein adds, "This is a time of extraordinary scientific opportunity."

The president's 2002 proposed budget includes $23.04 billion for NIH activities and programs—an increase of $2.8 billion, or 13.5%, over fiscal year 2001. Says Kirschstein, this "reflects the continuing commitment to doubling the NIH budget by 2003."

NIH plans to further expand its emphasis on clinical research. Several institutes will either initiate or enhance their clinical trials networks nationwide. To address the many issues created by the generation of more medical research data, current programs in bioinformatics and computational biology will also be expanded.

An NIH brief states that the president's budget request also supports NIH programs "to sustain the scientific momentum of investigator-initiated research and provide new research opportunities." The budget increases funding for extramural research activities by 12%. In addition, research and development contracts are increased by 20%.

Copyright ©2001 Medical Device & Diagnostic Industry

Curing system developed.

A microprocessor-based, high-intensity light-curing system is suited for both cleanroom and industrial use. The ELC-450, a product of Electro-Lite Corp. (Danbury, CT; 203/743-4059), uses a quartz-rod light-delivery device to cure objects that fit below the adjustable light tower. For applications requiring the use of a wand delivery system, any Electro-Lite liquid light guides will work satisfactorily. The system's high-contrast backlit display indicates the time, elapsed time, spent lamp hours, and lamp-ready status. The PC interface permits process validation and automated in-line control. ELC-450 is suited for medical device applications.