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Articles from 2011 In March


NIST Microreactor Could Lead to New Biodegradable Polymers

NIST Microreactor
A typical NIST microreactor plate measures approximately 40 x 90 mm cm. The channel, filled with plastic beads carrying the enzyme catalyst, is 2 mm wide and 1 mm deep. (Photo by Kundu, NIST)

Using a microfluidic device consisting of a small block of aluminum with a tiny groove carved in it filled with tiny beads, a team of researchers from the National Institute of Standards and Technology (NIST; Gaithersburg, MD) and the Polytechnic Institute of New York University (Brooklyn, NY) is developing an improved "green chemistry" method for making biodegradable polymers. The technology should be of interest to designers and developers of medical device materials.

The group studied the synthesis of polycaprolactone (PCL), a biodegradable polyester used in medical device applications. PCL, according to NIST materials scientist Kathryn Beers, is usually synthesized using an organic tin-based catalyst to stitch the base chemical rings together into long polymer chains. The catalyst is highly toxic, however, and has to be disposed of.

Modern biochemistry has found a more environmentally friendly substitute in an enzyme produced by the yeast strain Candida antartica, Beers says. However, standard batch processes in which the raw material and tiny beads that carry the enzyme are stirred together in a vat, is too inefficient to be commercially competitive. It also leaves an enzyme residue that contaminates and degrades the product.

In contrast, the NIST microreactor is a continuous-flow process. The feedstock chemical flows through the narrow channel of the microfluidic device around the enzyme-coated beads and emerges out the other end in polymerized form. This arrangement allows precise control of temperature and reaction time, so that detailed data on the chemical kinetics of the process can be recorded to develop an accurate model in order to scale the process.

"We basically developed a microreactor that lets us monitor continuous polymerization using enzymes," Beers explains. "These enzymes are an alternate green technology for making these types of polymers." Although the technology is not industrially competitive yet, data from the microreactor show how the process of developing biodegradable polymers could be made much more efficient. The team believes that their technology is the first example of polymerization produced using a solid-supported enzyme in a microreactor.

"The small-scale flow reactor allows us to monitor polymerization and look at the performance recyclability and recovery of these enzymes," Beers says. "With this process-engineering approach, we've shown that continuous flow really benefits these reactors. Not only does it dramatically accelerate the rate of reaction, but it improves your ability to recover the enzyme and reduce contamination of the product."

Klobuchar, Brown Assembling Medtech Caucus in Senate

 Apparently, Sen. Amy Klobuchar (D-MN) and Sen. Scott Brown (R-MA) aren't going to let Rep. Erik Paulsen (R-MN) and his Medtech Caucus buddies in the House have all the fun; Klobuchar and Brown have announced today that they are forming a medtech caucus of their own
 
Though they are from opposite sides of the aisle, Klobuchar and Brown seem to be simpatico when it comes to supporting medical device makers. They've come together to voice such support before, penning a letter together to try to influence FDA to keep industry in mind when evaluating 510(k) reform. Both represent states that are home to a large medtech presence, so it's not surprising to see them working together on this. 
 
Judging by the names that appeared on that letter in December, such as those of Sen. John Kerry (D-MA) and Sen. Al Franken (D-MN), I would guess that the group Klobuchar and Brown put together will include a mix of moderate Democrats and Republicans that have a vested interest in the device industry. So while the caucus will probably be in favor of repealing the notorious device excise tax, it will likely refrain from speaking out against healthcare reform with the vitriol of fellow device-tax critic and noted anti-"Obamacare" hard-liner Sen. Orrin Hatch (R-UT). As ever, it will be interesting to see how the various members of Congress continue to express their support for industry

—Thomas Blair

Fraunhofer Sees Future for Laser-Sintered Surgical Instruments

Fraunhofer laser-sintered surgical instruments
The Fraunhofer Institute thinks that surgical instruments with complex geometries and hollow channels can now be laser sintered.

Designers and developers of medical devices have questioned the suitability of laser sintering for certain applications, according to Philipp Imgrund, manager of the biomaterials technology department at Fraunhofer Institute IFAM (Bremen, Germany). For example, process repeatability and material selection have been problematic. But now, Imgrund says, the technology is here and ready.

Laser sintering enables manufactures to make surgical instruments of any shape, even if they involve complex geometries and hollow channels. The technology also allows manufacturers to build a cavity within the instrument to hold an RFID chip and encase it in metal without affecting signal readability.

Surgical instruments must be cleaned, sterilized, and inventoried after each use, and an integrated RFID chip is perhaps the best way to track them and ensure they have been properly processed. In a cast-metal product, however, the chip must have a small opening above it so that the signal can be read--an architecture that is not ideal in surgical instruments. In contrast, in laser sintered instruments, the RFID chip can receive and transmit data even though it is completely encased in a layer of metal. "Once the chip has been embedded in the instrument, there is no way to remove it short of performing a secondary production step," Imgrund stresses.

Although laser sintering has not yet been used to fabricate surgical instruments, its time has come, Imgrund comments. "Depending on the volume, of course, it can be very cost effective, since it requires no tooling, just a desktop system."

Portable Full-Body CT Scanner Gets FDA 510(k) Clearance

NeuroLogica Corp. has announced that its BodyTom portable, full-body CT scanner has received 510(k) clearance from US FDA. The 32-slice CT can be used in a variety of settings such as in the operating room, ICU, clinics and emergency/trauma departments. In addition, the manufacturer believes that technology could prove to be esoecially benefial to countries in the developing world. The device will be comercially available this year.



 

Hospital Groups Won't Share Device Tax Burdens

Everyone is worried about the tax on medical devices, including hospitals. HIll's Healthwatch blog says that hospital groups— the American Hospital Association, the Federation of American Hospitals, the Catholic Health Association of the United States and the Health Industry Group Purchasing Association—are asking the IRS to prohibit device manufacturers from passing the cost of the tax onto purchasers.

The device tax, which starts in 2013, imposes 2.3% excise tax on most medical devices to help pay for the Patient Protection and Affordable Care Act. 

The push from hospital groups comes on the heels of an 18-page letter to IRS from AdvaMed, which is worried that manufacturers could be subjected to double taxing. AdvaMed has asked the agency to clearly define the term manufacturer, because a broad definition could lead to a taxing of component and contract manufacturers. Including such manufacturers in the excise tax formula could have detrimental effects on small contract and component manufacturers.

Meanwhile, instead of a double tax, the Hospital Groups point to the possibility of a 'double dip' by OEMs in industry if IRS enables device makers to deduct the tax, even as they pass the cost along to hospitals. The groups suggest that device makers be required to verify on federal returns that excise tax costs were not transferred.

—Heather Thompson

Medical Device Excellence: The Divine Detail

Medical Device Excellence: The Divine Detail

Freedom LED: No Hands, No Wire

If you’ve been to the dentist lately (let’s hope you have) it’s likely that you sat under a very big and bright light. The person with their fingers in your mouth probably had to adjust that light a few times. Or perhaps the dentist or hygienist was wearing lighted headgear. You may not have noticed the cord running down her back—unless it snagged on a doorknob or a piece of equipment.

Orascoptic's Freedom LED head lamp clips on to any TTL loupe. Battery packs that hook onto the arms can support six hours of work. A touch switch turns the light on and off with the back of the hand.

The cordless Freedom LED head lamp from Orascoptic  provides enhanced visibility in combination with loupes. The goal for Orascoptic was to improve vision for dentists and hygienists examining, diagnosing, and treating dental work. (Check out a promo video about Freedom LED.) The device was designed by Bjorksten | bit 7 (Madison, WI).

The head lamp weighs 7 oz. and clips on to any through-the-lens loupe. The lightweight unit features rechargeable battery pods that securely fasten to the loupe’s temple arms. The battery pack is unique in that it helps to balance the lamp off the user’s nose. “The balance is very impressive,” says juror Craig Jackson, PhD, the retired president of Hemosaga Diagnostics Corp. (San Diego). The pod system charges quickly and provides 6 hours of energy life. It also eliminates the cord and pocket battery pack used in some head lamps.

Another feature that caught the jurors’ attention was how the unit deals with light switching. In most head lamps, push buttons or toggles control the lighting. In the Freedom, the designers decided to use a capacitive touch switch that can be operated by the back of a user’s hand. “The capacitive touch switch is brilliant,” says juror Stuart Karten, founder of Stuart Karten Design (Marina Del Rey, CA).

The touch switch improves work efficiency in that the dentist does not need to set down an instrument to turn on or adjust the LED headlamp intensity. It also improves hygiene because finger surfaces that work on a patient don’t touch the device.

Compass modular furniture from Herman Miller Healthcare is designed to fit into any space in a hospital, clinic, or work room. Each panel is coated with Durawrap to enable easy cleaning. Additional design details keep spills and splashes from seeping into cabinetry.

Compass: The Smartest Furniture in the Room

Wood, steel, PET, and aluminum are the components of Compass, a modular system of interchangeable cabinets and workspace that can be used to create applications for patient rooms, caregiver work areas, and other clinical spaces. But the cost-effective materials, 58% of which are recycled, are only one part of this well-thought-out system. Submitted by Herman Miller Healthcare (Zeeland, MI), Compass is designed to accommodate change, as well to cut costs for hospitals and contribute to patient comfort. The Herman Miller Design for the Environment team applied environmentally sensitive design standards, using the McDonough Braungart Design Chemistry Cradle to Cradle design protocol.

The Compass system is composed of horizontal mounting rails that attach directly onto the architectural walls of a patient room, exam room, or workspace. Vertical stiles attach to the rails and support the various tiles and storage components. Tiles and components are wrapped in Durawrap, a 99.9% PVC-free material that requires no edge banding, resulting in a seamless, cleanable, and durable surface.

“There are thoughtful details, down to insulation and cleaning procedures,” explains juror Sean Hägen, founder of BlackHägen Design (Dunedin, FL). Such attention to detail is largely a result of dedicated research. The design team conducted interviews with more than 550 clinicians, facility administrators, healthcare architects, and designers to determine their needs and the most important features for a system.

Researchers found that cleanliness was the most important requirement in the system's design. In addition to the Durawrap, tiles are designed to overlap in the horizontal plane to allow liquids to run down from one tile to the other. Liquids can’t gather in corners or hide between seams. In addition, the design mount floats above the floor, providing additional access to clean spills. Horizontal work surfaces are designed to allow liquids to drip to the floor for easy cleaning, and even the sink was designed with a raised lip to reduce splashing. “They have comprehensively covered maintenance issues, including spills and fluid management,” notes juror Anne Miller, an assistant professor at the Vanderbilt University Medical Center (Nashville, TN).

Besides having a clean surface, it was important to designers that the system looks clean as well. “The system dramatically reduces visual clutter, which translates into less stress for both patients and caregivers,” says juror Bryce Rutter, founder and CEO of Metaphase Design Group (St. Louis). Compass is designed and engineered to optimize the ergonomics for both the patient and the caregivers while providing a warm, healthcare-appropriate, and reassuring environment.

The modular design allows nurses and other clinical staff to make real-time changes to the patient room environment in response to changes in supply storage, patient acuity, or EMR introduction. These changes can be made with little downtime and without sending anything to a landfill.

JuggerKnot: Refining Tissue-to-Bone Connections

Various athletic injuries can result in soft tissues being torn from their original insertion site on the bone. The soft tissue repairs that occur adjacent to the articulating surfaces of a joint present a challenge because any aspect of the procedure that damages these surfaces can have devastating consequences to the patient. Minimizing the collateral damage and risks created by a repair is one of the primary goals of the JuggerKnot Soft Anchor. The JuggerKnot, created by Biomet Inc. (Warsaw, IN), is used during arthroscopic surgery or in sports medicine surgeries. The surgeon uses the suture to tie tissue to the bone.

The JuggerKnot from Biomet Sports Medicine aims to tie soft tissue to bone without causing additional articular damage. To do so, it replaces a bone screw with a suture, minimizing the drill hole size while creating a strong anchor.

To understand the advance of the JuggerKnot, we must first understand the standards of care that preceded the design. Several years ago, it was standard practice to create through-holes in the bone and suture tissue through those holes. But the technique posed a risk to neurovascular structures in addition to being time-consuming and complex. Suture anchors were then created as a means to connect suture to the bone without having to drill completely through the bone. These early anchor screws measured 3 mm in diameter and were made from stainless steel. The large size weakened bone structure and could cause collateral damage to other structures if the screw became dislodged. The drilled holes could also cause articular surface damage to the bone. Even after new materials were adopted such as PLLA, PGA, and PLDA, a lost anchor could damage articular cartilage, which could cause pain and early arthritis.

Biomet has changed the game with JuggerKnot, which uses a new technique that sutures soft tissue to bone with a suture instead of a screw. “This is novel engineering,” observed juror Clay Burns, who is vice president at Smart Design (New York City). “It places emphasis on cost efficiency and simplicity.”

A 1-cm strand of suture is combined with a standard suture used to tie down tissue passing through it along its central axis and stuffed into a small hole drilled in bone. Pulling back on the free strand of suture causes the smaller suture to bunch up, increase in diameter, and press against the rough wall of the bone hole.

Its simple design enables a 1.4-mm drill hole to be used thereby conserving a patients bone structure and reducing the risk to adjacent structures. Further, there are no eyelets or internal features to break, which means that the JuggerKnot anchor is stronger than previous anchor designs. Juror Peter Denk says: “It’s easy to use and has good bone interaction to promote healing.” The suture sleeve provides a low friction, soft, edge-free geometry for the tying suture to reside against, so failures due to suture breakage are mitigated.

An added benefit is that even if the anchoring sleeve were to pull out of the bone, it is made of suture, the same material already in contact with articular surfaces. It is therefore much less likely to damage such structures.

Coloplast A/S successfully juggles brand awareness and discretion with its SpeediCath Compact Male. The catheter is easy to carry, use, and dispose of.

SpeediCath: Discretion in All Things

Urinary catheters are not easy to live with or to design. They are difficult to conceal, awkward to store and carry, and take up space in the home and in transit. Enter the SpeediCath Compact Male from Coloplast A/S (Humlebæk, Denmark), a small, discreet, and sterile catheter that can be used in the home and on the go. It is less than half the size of a standard catheter and it features hydrophilic coating to reduce friction during insertion and removal.
The Coloplast design team created a catheter that fits into a patient’s pocket, has easy-to-open packaging, and can be disposed of conveniently.

“Design and engineering got it right,” Burns says. “This has tricky tooling and a good feel for parts and brand.”
Challenges for the company included choosing the right materials—a thin material that could withstand injection molding over a relatively long distance and accommodate simple manufacturing techniques. It also required considering the company’s existing branding message—Coloplast has a female catheter design already on the market.

PleuraFlow: Enacting the Laws of Simple Attraction

Much like the JuggerKnot’s simple and effective engineering, the PleuraFlow system struck a similar “Well, why didn’t I think of that?” note among the MDEA judges. The PleuraFlow catheter system from Tucson, AZ–based Xeridiem Medical Devices (formerly MRI Medical) is used during open surgical procedures and trauma (e.g., cardiothoracic procedures) to prevent fluid accumulation within the operative site after closure of the surgical wound. It is a tube clearance apparatus intended to prevent clogging and occlusion of chest tubes used for pleural and mediastinal drainage. Physicians insert and position the device into patients’ pleural space after thoracic surgery. It aims to solve the problem often met with postsurgical drainage. Research shows that patients think that the worst part of their chest surgery is the pain caused by having large tubes sticking out of their chest.

The PleuraFlow catheter system works to improve patient comfort and outcomes while reducing the burden on clinicians. Xeridiem Medical Devices' postsurgical tool removes clogs in chest tubes using magnets and other unique design elements.

The system comprises a curved silicone chest tube measuring 20 FR (less than 40% the size of standard chest drainage tubes) and a guide tube that is connected to a drainage canister. Inside the guide tube is a magnetically driven guide wire that advances into the chest tube. The wire can be advanced and retracted with in the chest tube to break up and remove tube obstructions or clogging.

Designing the curved device meant meeting various challenges, particularly how to advance the inner clearance wire to pull out clots. The magnet-driven system drew praise from several jurors. “The curved chest tube naturally adapts to anatomy and the magnetic mechanism is smart and unique,” explains juror Mary Beth Privitera, assistant professor at the University of Cincinnati.

The smaller incision contributes to patient recovery and reduces nursing care needs. Nurses were often required to squeeze out excess clogged fluids, a process that proved to be ineffective and cumbersome. The PleuraFlow claims to improve patient care and provide a better tool to clinicians for removing clogs postsurgery. Patient comfort is increased and the burden on medical staff is reduced. “It’s a simple idea that solves a complex problem,” says juror John Sinacori, an assistant professor in the department of otolaryngology at Eastern Virginia Medical School (Norfolk, VA).

Conclusion

Patients and users will never notice the details that have occupied the days and nights of the design teams that created devices singled out by MDEA jurors as examples of excellent design, and that is the point. If manufacturers pay attention to details, it means that users don’t have to. With the details out of the way, doctors, nurses, and other practitioners can give their full attention to treating patients, enabling them to concentrate on accelerating healing, improving quality of life, and decreasing pain.

Heather Thompson is editor-in-chief of MD+DI.

Medical-Grade Material Offers Clear Alternative for Rigid Packaging

Prent
Medex 641 (right) medical-grade rigid packaging material exhibits good clarity and a better yield per pound than polyester thermoformed trays (left).

Rising resin prices have prompted medical device manufacturers to put pressure on suppliers to provide more-economical packaging options. In response, custom thermoformed package provider Prent Corp. and its sister company, extruded plastics supplier Goex Corp., have introduced the medical-grade Medex 641 extruded styrenic alloy as a cost-effective alternative to XT polymer, polycarbonate, PVC, polyester, and other rigid packaging materials.

Prior to the development of Medex 641, Prent had focused on cutting material costs by reducing package weight through creative design and the use of down-gauged materials. "However, there is a limit to how thin deep-draw medical packages can become using existing materials," says Joseph Pregont, president and CEO of Prent. "We knew the success of such efforts would ultimately hinge on the development of new materials for medical packaging."

Following this realization, Prent established parameters and identified the desired properties of a clear, cost-effective, rigid packaging material. It then handed off the project to Goex for materials science and development work. Once the material was developed, Prent once again got involved by evaluating its performance during thermoforming and sterilization processes.

This several-year-long collaborative R&D process yielded a material that weighs less than competing packaging materials, according to Pregont. "With less density, you can achieve the same package with fewer pounds of material." As a result, total material costs are lower, and yields per pound are higher.

Along with reducing costs, achieving high clarity was paramount for the medical packaging material. "There were a lot of cost-effective alternative materials that were not clear," Pregont notes. "But the medical device industry really likes for end-users to be able to look through the package to make sure it's the correct package, to verify that everything is there, or to make sure that the package is intact before they open it."

Additional advantages of Medex 641 include strength and durability. Unlike some competing packaging materials, the styrenic alloy won't exhibit brittle failures, according to Pregont. Furthermore, it withstands E-beam, gamma, and EtO sterilization processes.

Medex 641 medical-grade material for rigid packaging is currently available in sheet form from Goex or in custom thermoformed trays from Prent.

Prent Corp.
JANESVILLE, WI
www.prent.com

Goex Corp.
JANESVILLE, WI
www.goex.com
 

Manufacturing Systems Today: Stent and Catheter Manufacturing

ASG Medical SystemsCatheter cutting, slitting, and flaring machine
The Accu-Flare CSF is the first machine to fully integrate cutting, slitting, and flaring of thermoplastic tubing into one process, according to its manufacturer, ASG Medical Systems. Capable of processing such materials as silicone, PTFE, and PEEK, the system features four operating modes: cut; cut and slit; cut and flare; and cut, slit, and flare. The cut-only mode has a length minimum of 1 mm, while the cut-and-flare length range is from 8 to 100 mm. Both the cut-and-slit and cut-slit-flare modes, on the other hand, feature a length range of 40 to 100 mm. Additional product features include full automation capability with feeding from the company's stick or spool feeders; a touch screen user interface with diagnostics, password-protected recipes, and machine parameters; and full bar code recipe setup, including tool tracking. The compact system is designed with a 50 × 50 × 35-cm footprint and weighs 25 kg.
ASG Medical Systems
WEST PALM BEACH, FL
www.asgmedical.com

Machine Solutions Inc.Automated stent-crimping system
Designed to perform automated PTCA stent crimping operations, the SC1775S system is optimized for high-volume manufacturers seeking advanced process control and integration with current MES. Manufactured by Machine Solutions Inc., the stent-crimping system is equipped with PLC control, an industrial PC HMI touch screen user interface, automated product handling, and networking capabilities. It is capable of storing up to 999 recipes and 20 stages per recipe. Postcrimp laser micrometer inspection, postcrimp image capture using a high-resolution camera, integrated bar code scanning, and integrated leak-detection options are also available. In addition, a proprietary film-head technology option protects drug coatings and polymer scaffolds during crimping. Product specifications include a crimp head length of 60 mm; an operating diameter range of 0.5 to 10 mm for thermoplastics and stainless steel; and an operating force range of 10-100, 20-200, or 20-300 lb. The system also features a diameter accuracy of ±0.25 mm, a force accuracy of ±1% of full scale, and a repeatability of ±0.4% of full scale.
Machine Solutions Inc.
FLAGSTAFF, AZ
www.machinesolutions.com

PlasticWeld Systems Inc.Catheter Hole-Drilling System
Suitable for catheter production, the HPD-6 semiautomatic hole-drilling system developed by PlasticWeld Systems features a stainless-steel cabinet and precision-machined components. Utilizing Oriental Motors linear actuators and Omron PLCs that can store up to 50 unique hole-pattern programs, the system has an intuitive operator program that enables virtually limitless combinations of hole patterns with distance and rotation inputs for each hole, according to the company. The system incorporates a proprietary collet clamping mechanism for positively orienting multilumen tubes and a blow-off and vacuum system for ejecting and capturing drilled tube slugs. With nominal dimensions of 24 × 24 × 19 in., an operating electric power of 110 V, and a compressed-air rating of 80 psi, the standard-configuration system can drill along a 6-in. length of tubing. Customized units can drill along tubes of any length.
PlasticWeld Systems Inc.
NEWFANE, NY
www.plasticweldsystems.com

VanteCatheter manufacturing system
Providing fast cycle times, repeatability, and a compact footprint, the semiautomated Saffire catheter manufacturing system from Vante consists of an RF generator and one of two forming platforms. The model 4200 RF generator features a large touch screen that allows operators to clearly view operating cycle parameters and temperature feedback. Selection of a forming platform is determined by insertion force requirements; the 4210H platform has a slide insertion force of 9.3 lb at 30 psi, while the 4210L unit has a slide insertion force of 3.2 lb at 30 psi. Capabilities of the system include taper, radius, soft, closed-end, and dilator tips; flaring; neck-downs; butt, overlap, and braid-to-nonbraid welds; single and multilumen tubes; balloon tips and welds; and marker band embedding and placement. It is suited for a variety of applications ranging from IV products to endotracheal tubes.
Vante
TUCSON, AZ
www.vante.com

Blockwise Engineering LLCStent-crimping machine
Suited for volume production, the PLC-controlled Model RHN stent-crimping machine provides process flexibility by allowing a sequence of diameter- or force-controlled steps defined in the selected recipe. Progression of steps can be automatic with programmable delays or programmed to wait for a user to press the index button or footswitch. In addition, each recipe may consist of 20 steps; up to 50 recipes can be stored in the PLC. At the core of the system is the High-Force Twin-Cam radial compression station featuring hardened stainless-steel dies that form a cylindrical opening ranging in diameter from 0 to 60 mm. Also integral to the system are a stepper motor that provides power to open and close the compression station, an integrated encoder that measures the diameter of the opening, and a force transducer that measures the actuating force. Available options include vacuum/pressure supply or heated dies.
Blockwise Engineering LLC
PHOENIX, AZ
www.blockwise.com
 

DLP Hyperspectral Imaging Technology Acts as Surgical GPS

A hyperspectral imaging system based on DLP chip technology can provide real-time mapping and visualization data to surgeons to reduce the risk of complications.

By applying an optical semiconductor technology commonly used in digital color projectors to an imaging technique employed by the defense industry, Karel Zuzak, senior biomedical research engineer at Digital Light Innovations (Austin, TX), has shed light on an array of potential optical medical imaging applications. The resulting hyperspectral imaging system could help reduce the risk of complications during various medical procedures and associated liability.

Providing chemical information about an imaged object, hyperspectral imaging entails the collection and processing of data from across the electromagnetic spectrum. Although proven useful in military air surveillance and other sectors, this particular ability to obtain information based on chemical data had not previously been explored in terms of potential medical applications. "The National Institutes of Health (NIH) had an interest in applying technology that had been used for defense to medical applications," Zuzak says. "It is of interest for using taxpayers' hard-earned money toward technology that is used to defend the nation as well as to bring better health to everyone."

Tasked with this ambitious research mission as a postdoctoral fellow at the NIH, Zuzak was able to develop a hyperspectral imaging technology using off-the-shelf components and by figuring out the math required for doctors to see better in the body. At the heart of the system, however, is the Digital Light Processing (DLP) development kit from Texas Instruments (Dallas), which features a DLP chip, software, and board electronics. Consisting of an array of tiny micromirrors mounted on a hinge that rocks back and forth like a seesaw, the DLP chip technology serves to control the different rainbow of colors in light or the spectrum in order to illuminate objects and determine their chemical composition, according to Zuzak.

"The DLP hyperspectral imaging method is a reflectance measure," Zuzak explains. "What this system does is actually illuminate a patient's tissue and collect information that is reflected back." Unlike the multispectral imaging technology at the heart of pulse oximeters, for example, the DLP hyperspectral imaging system does not require physical contact with the patient to gather information, Zuzak states. In fact, he adds, it can capture an image from a far-off distance or from mere inches away; however, a distance of two feet is typical. This ability is advantageous because the system does not need to compromise a sterile surgical area. In addition, it obtains chemically encoded images at a near-video rate of about four frames per second.

As a result, the platform-like imaging technology can provide real-time mapping and visualization data to assist surgeons with performing difficult procedures. Recent changes to reimbursement policy related to complications during gallbladder surgery, for instance, have created an increased demand for tools that help to reduce risk, according to Zuzak. Catering to this need, the DLP hyperspectral imaging system can act as an anatomical GPS of sorts, helping the surgeon to better navigate inside the body to avoid complications and risks.

"Surgeons are experts in anatomy from the textbook, which is the ideal case. But we're all different, and sometimes the vasculature just isn't laid out nicely; [vessels] will be twisted around each other, and the structures are embedded in connective tissue and fat," Zuzak notes. "Being able to identify the anatomical structures based on their chemical composition rather than just appearance is helping surgeons to see better inside the body."

In addition to aiding in gallbladder surgery, hyperspectral imaging technology is suited for a multitude of medical applications, including tissue oxygenation monitoring, wound healing, drug therapy monitoring, laparoscopic video imaging, noninvasive optical biopsies, diabetic retinopathy, retinal imaging, postoperative care, and personalized medicine. Zuzak and Digital Light Innovations are currently seeking OEM partnerships for implementation and commercialization of the technology into such applications.

Estimation of Average Bioburden Values for Low-Bioburden Products

A key aspect of the validation of a sterilization process, irrespective of the sterilizing agent, is an understanding of the product bioburden. This understanding must be both quantitative and qualitative; it’s important to understand both the number and types of contaminating microorganisms. The challenge to a sterilization process is related to both of these measures; high numbers of contaminating microorganisms and types of microorganisms with high resistance both pose a greater challenge to any sterilization process. Validation strategies for moist heat and ethylene oxide sterilization processes require this understanding of product bioburden—it is central to the bioburden-based approach and plays a key role in the combined bioburden/biological indicator approach to process validation.
 
Establishing a radiation sterilization dose is based on the product bioburden’s resistance to radiation. Biological indicators are not used in the establishment of a radiation sterilization dose and their use is contraindicated. Radiation dose establishment Methods 1 and VDmax of ANSI/AAMI/ISO 11137-2 require the determination of bioburden on product items from three product batches1. An average bioburden value is determined that is either the overall average for the three batches or the highest individual batch average if it is equal to or greater than 2× the overall average value. The indicated bioburden value is carried forward in these dose establishment methods and is used in a look-up table to identify a radiation dose to carry out the verification dose experiment. Clearly, for the verification dose value to be valid, the average bioburden value must be reliably estimated2.
 
A Problem with Low-Bioburden Products and Radiation-Dose Establishment
Many medical products currently being developed, particularly drug/device combinations, are manufactured under highly controlled conditions, a consequence of which is very low average bioburden. This is a good thing from the point of view of challenge to the sterilization process and the extent of treatment required to attain the required sterility assurance level (SAL). The problem arises when most or all of the product items have no recoverable bioburden in spite of using an efficient bioburden determination method with a validated recovery factor.
 
Table 1 gives the results of bioburden testing of three batches of product in preparation for the performance of a radiation dose establishment using Method VDmax; the data are formatted in the manner that was used by the testing lab. In the method applied, each product was immersed in an extraction fluid, agitated in a prescribed manner, and one-third of the extraction fluid was filtered through each of three 0.22-µm pore size membrane filters. Two of the filters were plated individually on soybean casein digest agar; one plate was incubated aerobically, and the second anaerobically. The third filter was plated on potato dextrose agar and incubated aerobically. After the specified incubation period, the colonies on the filters were counted and the results recorded. 
 
Table 1
Batch Number
Product Item
Aerobic
Anaerobic
Yeasts/Molds
CFU / Reported Value
CFU / Reported Value
CFU / Reported Value
1
1
0 / <3
0 / <3
0 / <3
2
0 / <3
0 / <3
0 / <3
3
0 / <3
0 / <3
0 / <3
4
0 / <3
0 / <3
0 / <3
5
0 / <3
0 / <3
0 / <3
6
0 / <3
0 / <3
0 / <3
7
0 / <3
0 / <3
0 / <3
8
0 / <3
0 / <3
0 / <3
9
0 / <3
0 / <3
0 / <3
10
0 / <3
0 / <3
0 / <3
Average
3
3
3
2
1
0 / <3
0 / <3
0 / <3
2
0 / <3
0 / <3
0 / <3
3
0 / <3
0 / <3
0 / <3
4
0 / <3
0 / <3
0 / <3
5
0 / <3
0 / <3
0 / <3
6
0 / <3
0 / <3
0 / <3
7
0 / <3
0 / <3
0 / <3
8
0 / <3
0 / <3
0 / <3
9
0 / <3
0 / <3
0 / <3
10
0 / <3
0 / <3
0 / <3
Average
3
3
3
3
1
0 / <3
0 / <3
0 / <3
2
0 / <3
0 / <3
0 / <3
3
0 / <3
0 / <3
0 / <3
4
0 / <3
0 / <3
0 / <3
5
0 / <3
0 / <3
0 / <3
6
0 / <3
0 / <3
0 / <3
7
0 / <3
0 / <3
0 / <3
8
0 / <3
0 / <3
0 / <3
9
0 / <3
0 / <3
0 / <3
10
0 / <3
0 / <3
0 / <3
Average
3
3
3
Total Average Bioburden = 9  
No colony-forming units (CFU) were observed on any of the filters. Because only one-third of the extraction fluid was filtered onto any membrane filter, the result recorded for each plate was < 3. The problem comes with the calculation of the average bioburden—each of the < 3 entries was treated as 3, and an average of 3 was declared. As the average value was 3 for aerobes, anaerobes, and yeast/molds, the total average bioburden for each of the three batches of product was declared to be 9, and an overall average of 9 was declared for the three batches. The value of 9 was carried forward into the VDmax look-up table to determine the verification dose. It is important to reiterate that no CFU were observed on any of the plates.
 
The conclusion that each of the product batches had an average bioburden of 9 is neither reasonable nor statistically tenable. If the average bioburden for aerobes were in fact 3, the total number of CFU that would have been expected to be observed would be 30 on the aerobically incubated plates (the actual number of CFU expected to be recovered is 90, but only one-third of the volume was filtered, so 30 would be the observed value). A finding of no CFU for the 30 product items is not reasonable and a Poisson Distribution calculation gives a probability of ~10-13 for a finding of 0 CFU with an expected average of 30 CFU.
 
What is the proper estimate of the average bioburden in this situation? A value of 9 is clearly not a good estimate and the bioburden is most likely not zero either. The average bioburden is clearly < 9, but how much less than 9?
 
Treatment of < Values
One approach for calculating an average bioburden estimate for the case described above is based upon the Poisson Distribution. The total number of CFU observed for "aerobes" for a given product batch was zero. The 95% upper confidence limit (UCL) for an observation of zero, using the Poisson Distribution, is 3. For each product batch, with a dilution factor of 3, the calculated average bioburden estimate would be (3/10)*3 or 0.9 CFU. If this approach were applied to all of the results for aerobes, taking into account all three batches of product, the calculation would be (3/30)*3 or 0.3 CFU. This value is statistically tenable. If 0.3 were the true overall average value, again with a dilution factor of 3, the total number of expected CFU for the 30 plates would be 3 ((0.3*30)/3). The 95% lower confidence limit for an average value of 3 is zero. Another way of looking at this latter calculation is to frame it as the count found in 100% of the filtrate from 10 products rather than one-third of the filtrate from 30 products. The calculation becomes simply 3/10 or 0.3. For a single batch, filtrate equivalent to 3.33 entire products is tested so the calculation can be framed as (3/3.33) or 0.9.

This approach can be readily applied to any combination of numerical and < results. For each batch of product and each test condition (aerobic, anaerobic, yeasts/molds), add the total number of CFU observed and to this sum add the value of 3 if one or more products has no recovered bioburden. This is shown in Table 2.

Table 2
Product Item
Case 1
Case 2
Case 3
CFU 
 
1
1
0
0
2
1
0
0
3
1
1
0
4
1
0
0
5
1
1
0
6
1
1
0
7
1
1
0
8
1
0
0
9
1
1
0
10
1
1
0
 
Total Observed CFU
10
6
0
Corrected Total CFU1
30
27
9
Corrected Average Bioburden
3
2.7
0.9
1Corrected Total CFU = 3*((Observed CFU)+(3 if ≥ 1 product item has no recovered CFU)) 
In Case 1, CFU are observed on each of the plates and the average bioburden value is accordingly the arithmetic mean of the total number of CFU observed (appropriately multiplied by any dilution or recovery factors). In Case 2, four of the plates were found to have no CFU; 3 was added to the total number of CFU observed and the calculation of the average made. Case 3 is the example in Table 1 where no CFU are observed on any on the plates. Note that if the approach used in Table 1 had been used for Case 3, an average bioburden of 3 would have been declared. This value is inconsistent with the results of Case 1 where the same average was determined based on the observation of a total of 10 CFU.
 
"Censored" Data Approach Substitution
Experimental data that are termed "censored" are outcomes that are below or above a limit of detection (LOD), either due to capability of the method being used or the nature of the experimental design. An analytical method might have a lower LOD of 10 parts per million (ppm). A test result where the analyte in question is not detected would be recorded as <10 ppm. The point that is not clear is how much less than 10 ppm is the true result.
 
An example that involves experimental design is the determination of the number of runners who finish a marathon in a time between 3 and 4 hrs. An observer could watch the entire race and have a time value recorded for all runners; in this case there would be no censored data. Or, the observer could arrive at the finish line just at the 3-hour mark and depart right at the 4-hour mark. In the first case, calculating the average finishing time for all runners in the race would be straightforward. In the second case, there would be considerable censored data. A number of runners would have their time recorded as either < 3 (“left-censored” data) or >4 hours (right-censored data).
 
An approach that can provide a good estimate of the average result for a data set with left-censored data is to substitute one-half of the LOD for each < value3. This substitution is most appropriate when 50% or less of the values are censored. The data shown in Table 2 were analyzed using this approach and the results are shown in Table 3. As can be seen, the result for Case 2 is similar to that shown in Table 2. The result for Case 3 is markedly higher using the one-half LOD approach. Such an outcome is expected when all of the data from a given test are censored.
 
Table 3
Product Item
Case 1
Case 2
Case 3
CFU 
 
1
1
0
0
2
1
0
0
3
1
1
0
4
1
0
0
5
1
1
0
6
1
1
0
7
1
1
0
8
1
0
0
9
1
1
0
10
1
1
0
 
Total Observed CFU
10
6
0
Corrected Total CFU1
30
24
15
Corrected Average Bioburden
3
2.4
1.5
1Corrected Total CFU = 3*((Observed CFU)+(0.5*number of product items with no CFU recovered)) 
 
Comparing the Two Approaches
Figures 1 and 2 compare the results when the two approaches discussed above are applied. In these examples, each product has either zero or one CFU. The results cover the range from none of the products having any recovered CFU, to all of the products having 1 CFU.
 
As shown in Figure 1, when no or few CFU are recovered from the 10 products, the one-half LOD substitution for the censored data gives a higher estimate of the average bioburden value. As the number of products with observed CFU increases, with consequently fewer results that are “0,” the average values estimated by the two approaches converge and then diverge as the number of products with recovered CFU increases further, to a final convergence when no results are “0.”
  
Figure 1: Shown is a plot of the estimate of the average bioburden for a group of 10 products that each has either 0 or 1 CFU recovered, with a dilution factor of 3 and a recovery efficiency factor of 1.
 
Figure 2 compares the two approaches using the results of testing 30 products as in the calculation of the overall average bioburden for three lots of product, 10 products tested per lot. The same outcome is observed as seen above, but in this case, the average bioburden estimate given by the two approaches yields the same value at a lower fraction of products with no CFU recovered. This effect is caused by the substitution, by the Poisson approach, of a value of 3 CFU which, on average calculation, is distributed over a larger number of products compared to the case illustrated in Figure 1. The one-half LOD substitution assigns the same value to each product with no recovered CFU, regardless of the number tested.
 
Figure 2: This plot shows the estimate of the average bioburden for a group of 30 products that each has either 0 or 1 CFU recovered with a dilution factor of 3 and a recovery efficiency factor of 1.
 
 
A simple Excel spreadsheet has been developed to calculate average bioburden estimates for data sets with “<” values. Required inputs are the number of product items tested, the total number of CFU observed, the number of products with no recovered CFU, the dilution factor, and the recovery efficiency factor. The bioburden estimate is calculated by both approaches and the results compared. The lower of the two values is taken as the best estimate of the average bioburden from the inputs supplied. A screenshot of the worksheet is shown in Figure 3.
 
 
Figure 3: This calculation estimates the average bioburden using Poisson Distribution-based and one-half LOD-based substitution approaches. It shows a test of ten products, each of which has no recovered CFU, and a dilution factor and recovery efficiency of 1.
Number of Product Items Tested = 10
Fraction of Eluate Tested Per Item = 1
Total Number of CFU Recovered = 0
Number of Product Items with No CFU Recovered = 10
Recovery Efficiency Factor = 1
"Poisson Substitution" Average Bioburden = 0.30
"One-Half LOD Substitution" Average Bioburden = 0.50
Average Bioburden Estimate = 0.3
 
Optimizing Bioburden Recovery Methods
Clause 7.2.3.2 of ISO 11137-2 notes that for products with a low average bioburden, multiple products may be pooled and tested together in the same extraction vessel. If ten products were tested in this manner and a total of 15 CFU were recovered on the aerobic plates, a batch average bioburden of 1.5 CFU could be inferred for aerobes, assuming all of the extraction fluid was assayed and the recovery efficiency factor was 1.
 
The use of a pooled sample method requires that a recovery efficiency be determined for that approach and it’s important to note that there is also a loss of information with respect to bioburden distribution from item to item. In the example above, was there a low CFU level on most of the ten products, or did one product have 15 CFU and the others none?
 
Combining/Eliminating Tests
In too many instances, manufacturers default to a "four way" bioburden test: aerobes, anaerobes, yeasts/molds, and aerobic spores. To accomplish this test approach, the extraction fluid is divided into at least four parts which automatically results in a dilution factor of 4.
 
In most cases, testing for spores generally brings little added value. The presence of spore-forming microorganisms can be readily determined during simple identification testing on the bioburden recovered on the aerobic plates. If an election is made to test for spores initially, this test can be subsequently eliminated unless some particular value has been demonstrated.
 
Similarly, testing for anaerobes generally brings little value. Most synthetic medical products are free from strict anaerobes, and the CFU recovered on the plates incubated anaerobically are facultative microorganisms that are also being recovered on the plates incubated aerobically. Caution must be exercised, however, when bioburden is being recovered from human or animal tissue or other natural products such as plant-derived materials. Ongoing recovery of strict anaerobes, possibly in high numbers, can occur.
 
With an injection-molded polymeric device, there’s generally no point in continually testing for anaerobes if strict anaerobes are either not found or found only occasionally in low numbers. Also, the presence of anaerobic conditions doesn’t necessarily mean the presence or potential for growth of strictly anaerobic microorganisms. Products made from absorbable polymers are often stored under dry nitrogen to protect them from oxidative- and/or moisture-related damage. Being a synthetic polymer, contamination with strict anaerobes is highly unlikely and storage in dry nitrogen doesn’t provide an exogenous source of the nutrients and moisture required for microbial growth.
 
Testing for aerobes and yeasts/molds is always important and the dilution factor can be eliminated by combining the two tests. The entire extraction volume from each of 10 products can be assayed on a general-purpose growth medium, such as soybean casein digest agar. The plates are incubated at 30° to 35°C for 48 hrs., and the incubation continued at 20° to 25°C for an additional 72 hrs., then the plates are counted4. If testing for spores isn’t desired and testing for anaerobes has shown that this testing isn’t indicated or required, a bioburden determination can be performed with this one test, thereby eliminating a dilution factor that can artificially inflate the average bioburden value.
 
In practical terms, for a test involving 10 products that’s conducted in a manner so there’s no associated dilution factor, the minimal batch average bioburden that should be claimed is 0.3 CFU. This outcome would be from a result of zero CFU recovered in a test that had a recovery efficiency of 1. The conversion of 10 outcomes recorded as “< 1” into an average of 1.0 is not statistically supportable—a finding of zero CFU with an expected value of 10 CFU has a probability of ~4.5 × 10-5. Use of the one-half LOD approach would yield an average bioburden estimate of 0.5 CFU.
 
Implications of These Approaches
The bioburden data in Table 1 are actual results. In fact, this data set and the conclusion with respect to the average bioburden was reviewed in a recent audit by a Notified Body and challenged as being an overestimation of the true product bioburden and the validity of the associated dose-establishment exercise was seriously questioned.
 
Drug/device or convergent technology products made in highly controlled manufacturing environments, often with presterilized components, are likely to have very low bioburden. An accurate estimation of the bioburden is important in sterilization process validation studies, particularly with radiation sterilization. With either Method 1 or Method VDmax, higher average bioburden translates to a higher minimum sterilization dose.
 
Once the challenge has been met with respect to manufacture of a product with low bioburden, an overall methodology must be used to give an accurate determination of the average bioburden. The first instinct would be to perform a traditional bioburden determination as described in Table 1, the testing of 10 products from each of three production batches. A pooled sample, or a most-probable-number (MPN) approach, isn’t common in initially-used methods for bioburden determination. The pooling of product units into one test can obscure item-to-item bioburden variability, and the results of the MPN approach lack information on the bioburden level for any nonsterile product units.
 
For products with a low average bioburden, the Poisson Distribution-based substitution for the “less than” values gives a bioburden estimate that’s statistically tenable. The one-half LOD substitution is less appropriate in some cases as it leads to an overestimation of the bioburden as the number of product items with no recovered CFU increases. Use of the Poisson Distribution-based substitution approach will yield an average bioburden value that can be carried forward to the “look-up” table in Method 1 or Method VDmax to identify the appropriate radiation dose for the verification dose experiment. Such an average bioburden value, and the consequential verification dose, will have a statistical underpinning and will avoid/withstand technical/regulatory challenge.
References
1. Sterilization of health care products — Radiation — Part 2: Establishing the sterilization dose, ANSI/AAMI/ISO 11137-2:2006, Arlington, VA, Association for the Advancement of Medical Instrumentation, 2006.
2. Sterilization of medical devices — Microbiological methods — Part 1: Determination of a population of microorganisms on products, ANSI/AAMI/ISO 11737-1:2006, Arlington, VA, Association for the Advancement of Medical Instrumentation, 2006.
3. Clarke, JU, “Evaluation of censored data methods to allow statistical comparisons among very small samples with below detection limit observations”, Environ Sci Technol 32:177-183, 1998.
4. Marshall V, Poulson-Cook S, Moldenhauer J, “Comparative mold and yeast recovery analysis (the effect of differing incubation temperature ranges and growth media),”  PDA J Pharm Sci Technol, 52(4):165-169, 1998.
 

Dr. Harry F. Bushar is a statistical consultant for FDA/CDRH/OSB/DBS, where he was previously employed as a mathematical statistician. 
 
Dr. John B. Kowalski is a principal consultant with SteriPro Consulting, a division of Sterigenics International.
 
Gregg Mosley is an internationally recognized authority in GMP compliance, sterilization, and manufacturing of sterile medical products.