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Great Pretenders: Polymer Creates Blood Cell Mimics for Drug Delivery

By mimicking the flexibility of real blood cells, imitation cells made from a polymer can be used for drug release to places that normal mechanisms just can’t get to. The delivery method could also be used for contrast agents for medical imaging or to replace a blood transfusion.

These devices can squeeze through spaces smaller than their own diameter, just as real cells do. A concaved tire shape is what enables blood cells’ flexibility. In the body, blood cells start out as spherical cells, which then collapse into mature red blood cells following exposure to various substances.

To create synthetic particles that have the same ability, researchers at the University of California, Santa Barbara, add small balls of a PLGA polymer to a solvent, causing the spheres, which measure about 7 μm across, to collapse into a biconcave shape. The researchers coat the particles in a layer of protein. Then the polymer core is dissolved, leaving a pliable biodegradable protein shell that has mechanical properties similar to red blood cells.

The implications of the technology could be far reaching. For example, researchers are exploring how to use these shapes for drug delivery to targeted areas at a more constant concentration. The team exposed the shapes to heparin to show that they can carry drugs. Heparin was absorbed and the protein shells released the drug when they were moved to an area of lower concentration. Substances such as iron oxide nanoparticles that increase contrast in magnetic resonance imaging could also be delivered. The researchers have also experimented with sickle-cell blood shapes to see whether they can learn more about how the misshapen blood cells travel through the body.

Even more astounding, the particles could be used for blood transfusions. Researchers conducted in vitro experiments and found that hemoglobin-coated particles picked up oxygen in an oxygen-rich environment and released it later when the concentration was lower. If the particles do the same thing in vivo, they could be used in place of traditional transfusion.
 

Making Minimotors with Paper: Just Add Liquid

Purdue University (West Lafayette, IN) researchers have developed an inexpensive way to make miniature motors and actuators using paper and liquid ferrofluid that contains magnetic nanoparticles. The resulting micromotors could be used in minimally invasive surgical instruments. 

Babak Ziaie, professor of electrical engineering at Purdue, says the process is very simple. “All you need to do is put a drop on the paper. The paper soaks it up, and there you are,” says Ziaie, adding that the appeal of the technology is the inexpensive process. The method used to create this paper doesn’t require special lab facilities either, and according to Ziaie, a high school student could make it.

The researchers first used scissors to cut the paper. However, laser machining makes shapes that are more complicated and smaller—as small as 100 μm.

The process begins by impregnating regular paper with mineral oil and iron oxide magnetic particles, which are commercially available. Ziaie recommends newspaper and soft tissue paper due to the porous nature of those materials. To provide resistance to water and fluid evaporation, the paper is coated with a biocompatible plastic film. The coating enhances the strength, stiffness, and elasticity of the paper, which is called ferropaper because of its relation to iron.

For biomedical applications, the softness of the paper is useful in cases in which a lot of force shouldn’t be applied, such as for tissue cultures. And although it could be difficult to use the ferropaper to make motors for surgical instruments, it’s not impossible, says Ziaie. “[Devices] that are easier [to make] are grabbers, or small tweezers, that you can remotely activate with a magnetic field.” Such grabbers would be used to touch and manipulate sensitive tissue during a minimally invasive procedure such as an eye operation.

The researchers used the ferropaper to make a cantilever actuator, which is moved using a magnetic field. Ziaie says that although cantilever actuators are common, they’re usually made from silicon, which is much more expensive than the ferropaper and requires a special facility for the manufacturing process.

The next step is to create an easier way to integrate the ferropaper into a substrate. “If you want [the ferropaper] it to be more useful, you have to be able to attach or integrate it into other materials like polymers or silicones,” says Ziaie.

The researchers are currently working on licensing the technology to a company. At press time, they were filing for patent protection. They presented their research at the 23rd IEEE International MEMS conference in Hong Kong.

Device Industry Assistance in Haiti Continues

Shortly after the earthquake hit, Covidien sent wound dressings, surgical kits, and gauze to Haiti for distribution. The company will also be delivering a significant donation of pain medications to the region through its pharmaceuticals segment. Through a partnership with Project HOPE, Covidien is providing products for the USNS Comfort, a floating hospital, and the company has donation partners in Haiti and the Dominican Republic in order to supply sutures, patient monitors, and other devices to the area. The company is also matching employee contributions of $25 or more dollar-for-dollar within the United States and is making company contributions to supplement employee donations in other regions of the world, according to Lisa Clemence, media relations manager at Covidien.

Philips Healthcare has been working with Project HOPE and Caritas Christi Health Care to send medical equipment to Haiti. Due to the extensive damage to the main airport in Port-au-Prince, the company found logistics partners CAS Xpress and IBC Airways to fly products into Cap Haitien, which is an airport located on the north coast of Haiti. "In Andover, employees pulled together intensive care monitors, surgical monitors, fetal monitors, vital signs monitors, cardiographs, defibrillators, ventilators, and medical supplies for shipment," according to senior mechanical engineer Daryl Schilke. "On Tuesday, January 19, in the midst of a snowstorm, a Fedex truck pulled out of Andover’s loading dock with 21 pallets of equipment and supplies worth almost $1 million. In addition to that shipment, we are now sending mash unit tents and cots for additional patient needs." Once the products from Philips arrived in Haiti, they were set up at Hopital Sacre Coeur, a 70-bed facility in Milot that is about 70 miles from Port-au-Prince. According to Schilke, the hospital has been receiving patients via U.S. Coast Guard helicopters. It has two operating rooms, a fully-equipped lab, and can house 75 to 100 medical personnel. "It certainly wasn’t easy to get nearly $1 million of equipment and supplies to Haiti in just one week. Hundreds of Philips employees throughout the world worked around the clock to make this happen and cleared many hurdles along the way," says Schilke. "Philips’ mission as a company has always been to improve people’s lives. We can all be proud that we have lived up to that mission for the people of Haiti." --Maria Fontanazza

Italian Researchers Create Synthetic Bone from Wood

A method for turning rattan wood into a substance that bonds with natural bone could soon be used to create transplant material for humans. Italian scientists, led by Anna Tampieri at the Istituto di Scienza e Tecnologia dei Materiali Ceramici (ISTEC) based in Faenza, Italy, created the material. The researchers start by cutting long tubular rattan wood into small pieces. Then, a complex chemical process fuses the material with phosphate and calcium.

After being heated in a furnace, the pieces are reheated under intense pressure in another machine similar to an oven. The end result is a material that is nearly identical to bone. Under a microscope, a cross section of the material has a similar structure to natural bone. After implantation, the small pores in the substance allow blood and nerves to migrate from surrounding bone.

Tampieri said the new bone material is strong, so it can withstand the heavy load of a human body. She also said that tests have demonstrated the materials’ durability, so, that “unlike existing bone substitutes, it won’t need replacing.”

The material is being used experimentally at Bologna University’s hospital, where orthopedic surgeons such as Maurillo Marcacci are monitoring its effects in sheep. X-rays of the sheeps’ legs indicate that particles from the sheeps’ own bones are migrating to rattan-based bone. Testing indicates that the real bone and the implant fuse within a few months into a continuous bone.

Observing no signs of rejection or infection in the sheep, the scientists hope that rattan presents a natural, inexpensive, and effective replacement for bones. The researchers note that implants into humans are about five years away.
In contrast to this artificial wood-based bone, existing bone substitutes such as metal, ceramic, or bones from cadavers all have their drawbacks, Marcacci noted. For people with major trauma injuries or cancer, the current range of alternatives is often limited. Materials currently available do not fuse with the existing bone. “A strong, durable, load-bearing bone is really the holy grail for surgeons like me and for patients,” he added.

Detecting Nitinol Surface Inclusions

In recent years the use of nitinol (an almost equiatomic binary intermetallic compound of nickel and titanium) has been steadily growing, particularly in the medical and dental device markets. Nitinol-based medical devices can be divided into two groups: implantables (e.g., peripheral stents, cardiovascular luminal shields, and heart valves) and surgical tools (e.g., stone and blood clot retrievers, vena cava filters, and endoscopes). Dental devices that make use of the alloy include endodontic rotary files and orthodontic archwires.

The main reasons for this growing use of nitinol arise from its combination of mechanical (pseudoplasticity and shape memory) and biocompatible properties. Nitinol can undergo reversible change between two crystal structures. In addition, it spontaneously creates titanium-rich oxide. Some research has shown that titanium-rich oxide on nitinol stents can minimize the formation of fibrin- and platelet-rich thrombus.1
 
There has been some effort by nitinol producers and scientists around the world to develop almost totally passive inclusion-free nitinol, with improved fatigue and corrosion resistance properties. Some of these approaches include smart anodization, acidic and basic chemical etching, heat treatment in a different gaseous atmosphere, ion implantation, cryogenic treatment, electropolishing and magnetoelectropolishing.2,3 However, these methods do not place emphasis on homogeneity and, therefore, cannot guarantee an inclusion-free surface.
 
Table I. Origin inclusions are easier to identify than chemical inclusions. Chemical analysis can often lead to errors.
Some research has shown that about 80% of crack initiations in nitinol stents are triggered by visible inclusions.4 In response to this research, nitinol producers in Europe offer what is called extra-low-inclusion nitinol (such as that supplied by Euroflex). Nonmetallic inclusions have been frequently shown to be corrosion and crack initiation sites in superelastic nitinol.5 Surface inclusions cause stress during rotational bending and flexing (particularly for peripheral stents) and can lead to fracture.6 In addition, the inclusions and nonhomogenous adjacent matrix are thought to act as sources for corrosion and can release harmful nickel ions to surrounding living cells, which can create inflammation or stimulate intimal hyperplasia in implanted peripheral nitinol stents.7
 
It should be noted that there is some controversy attached to the topic of this article, in that some leading experts in the field do not agree with the description of overall nitinol surface inclusion problems or the premise of the test proposed. However, academic pursuits, particularly those of Svetlana Shabalovskaya, associate of the Ames Laboratory at Iowa State University, indicate some validity. Her research, along with others who have been researching problems of nitinol surface inclusions for the past several years, shows that inclusions are not trivial and calls for further study.
 

Inclusion Classifications

Nitinol inclusions are classified in two ways: by origin and chemical composition. Classification by origin gives two kind of inclusions: native (introduced during production of bulk material) and foreign (introduced during pro­cessing and finishing of detailed medical devices). Native inclusions are distributed throughout the whole volume of the material including surfaces. In contrast, foreign inclusions are strictly surface phenomena (see Table I). Classification by chemical composition is more complicated.
 
Because of the very small size of inclusions, chemical analysis is difficult and often leads to errors. Chemical inclusions could be broadly classified as carbides (TiC), oxides (Ti4Ni2Ox, TiO2) or intermetallic precipitates (Ni4Ti3, Ni3Ti).8,9 It is widely recognized that carbides are primarily created during vacuum induction melting (VIM), for which graphite crucible is the source of carbon. Oxides are created in larger amounts and in larger particle sizes during vacuum arc melting (VAM) than during VIM. A third process, which claims 4–10 times lower carbon content due to use of water-cooled copper crucible, is electron beam melting (EBM).10 Although these methods of nitinol production are widely used, none of them produce 100%-inclusion-free homogenous nitinol.
 
 
Figure 2. Nitinol wires after one week of submersion in 6% NaClO. On the left is an inclusion free surface. The right shows surface inclusions.
It is worth mentioning that native, as well as foreign surface inclusions, undergo physical changes under mechanical production processes such as stamping and drawing. Those physical changes consist of fragmentation of inclusions under mechanical force. For example, the drawing process breaks down transverse inclusions, making them smaller as the diameter of the wire or tube reduces. Longitudinal inclusions break down and form strings of smaller inclusions that are elongated in the direction of drawing process (see Figure 1). This phenomenon carries both benefits and drawbacks.
Small-diameter wires and tubes have better fatigue resistance than larger parts because small inclusions are less likely to initiate fatigue cracks. There is also a higher probability of developing corrosion and nickel leaching sites from multiple inclusions spread over a large surface area. The high number of corrosion sites decreases the probability of stopping the corrosion process by repassivation.
 
Local martensitic transformation and stress concentration points are other problems that can be created by inclusions. For example, the creation of titanium carbide (TiC) inclusions drains titanium from adjacent matrices. 8, 11–13 The matrix depleted of titanium will change its martensitic transformation temperature compared with the rest of material, which can lead to unexpected voids and crack initiation.
 

Testing for Inclusions

The most common ways to test nitinol surfaces for inclusions require instrumental observation techniques. These techniques are transition electron microscopy, Auger electron spectroscopy with back scatter electron detection, scanning electron microscopy with energy-dispersive x-ray spectroscopy, atomic force microscopy, and x-ray diffraction (XRD). All of these techniques are expensive and time consuming. They demand highly trained operators and sophisticated equipment, and they are neither effective nor practical for mass inspection on an industrial scale. To overcome the inability to check every nitinol-based implantable device (especially peripheral stents) for surface inclusions before implantation, a chemical test has been developed, which is currently pending U.S. patent. The chemical test is simple and resembles the old but still-used ASTM standard A262 copper-copper sulfate test for testing stainless steel for ferrite formation. The inclusions test uses 6% sodium hypochlorite (NaClO) as a reagent and requires 15 minutes of immersion and observation to conclude presence or absence of surface inclusions.
 
Figure 3. Inclusion-free nitinol wire after six months of exposure to a 6% solution of NaClO.
As long as the interatomic bonds between nickel and titanium in nitinol are intact, the intermetallic compound stays totally inert when exposed to aqueous solution of NaClO. But when those bonds are broken by precipitated inclusions, the nitinol becomes prone to corrosion by NaClO. The mechanism of this corrosion arises from the aggressiveness of NaClO toward nickel. When nickel is exposed to NaClO, a chemical reaction starts immediately. It continues until all nickel is dissolved or NaClO is spent according to the chemical reaction as follows:
 
2Ni + 3NaClO + 3H2O → 2Ni(OH)3 ↓ + 3NaCl
 
The visual sign of this reaction is black flocculent precipitate of Ni(OH)3 ↓.
 
When homogenous, inclusion-free nitinol surface is exposed to NaClO, nothing happens (see Figure 2 and Figure 3). Spontaneously (by ambient atmosphere) or artificially (by electropolishing process for example) created TiO2 efficiently protects nitinol against corrosion. Even if the nitinol is broken when submerged in NaClO, if the broken surfaces do not contain inclusions, corrosion does not start. Because freshly broken inclusion-free surfaces do not possess sites enriched in nickel atoms, the NaClO spontaneously oxidizes the surface to create TiO2, which prevents corrosion. In addition, inclusion-free electropolished nitinol surfaces are not attacked even during boiling in 6% NaClO. The surface also retains the reflective quality from the electropolishing. But if nitinol possesses surface inclusions, corrosion starts almost immediately. Characteristic black flocculent oozes from the reaction site (see Figure 2, right), which is inseparable from effervescence of oxygen gas O2↓ according to the following reaction:
 
9NaClO + 2NiTi + 7H2O → 2Ni(OH)3↓ + 2Ti(OH)4↓ + 9NaCl + O2
 
The dissolving nickel can come from two sources. The first is from the matrix surrounding inclusion, which is enriched in nickel during the process of creating inclusion by draining titanium elements to create inclusion as TiC, for example. The other source is the inclusion itself, which is enriched in nickel (e.g., intermetallic inclusions of Ni4Ti3, Ni3Ti created during wire drawing operation). But it does not matter from which source Ni(OH)3↓ originates because both sources indicate the presence of inclusions and nonhomogeneous nitinol. Titanium hydroxide, Ti(OH)4 (white precipitate) also originates during corrosion reaction, but is masked to some extent by the black color of Ni(OH)3, although it can be seen with the naked eye. These two separate corrosion reaction products, with their distinguished colors, are indicators that nonhomogenous nitinol dissolves separately as nickel and titanium and not as an intermetallic compound (see Figure 4).
 
Figure 4. Nitinol wire corroded in places of inclusions. The white precipitate is titanium hydroxide and the black precipitate is nickel hydroxide.
Sporadically an intermediate green compound of NiCl2 × 6H2O is formed (see Figure 5). This phenomenon is not yet fully understood, but probably depends on the chemical composition of a particular inclusion. These three precipitates (distinguished by color) originate at the inclusion sites and are released in the presence of NaClO. It is worthwhile to mention that XRD analysis of precipitate of dissolved nitinol has detected only one compound as crystalline—namely NaCl—and the rest of materials were in amorphous form. This finding is also proof that NiCl2 × 6H2O is an intermediate compound because the compound possesses crystalline structure but was not detected by XRD.
 
Until now, only instrumental techniques have been available to check nitinol for the presence of surface inclusions and these are used for research purposes. Those methods are complicated, expensive, and not applicable in all cases (e.g., 3-D and complicated shapes). For those reasons, they are not used as inspection tools to check nitinol surface inclusions of finished medical devices. Currently nitinol-based implantable devices such as peripheral stents undergo optical inspections (e.g., by the computer-assisted automated stent inspection system from CTR Carinthian Tech Research AG), but those techniques are not able to detect surface inclusion. They can detect defects that measure 200 µm and larger, but 200 µm is far beyond the size of an average inclusion.
 
Figure 5. Nitinol wire with intermediate corrosion product showing a green precipitate of NiCl2 × 6H2O.
The chemical test enables analysis of both raw material and finished products. In the event of positive test results of raw material intended for production, material can be rejected before starting expensive manufacturing processes, thereby saving money and time. The postproduction test of finished products can eliminate defective products, thereby limiting the risk of serious or life-threatening problems (such as fracture of endodontic rotary files, carotid stents, heart valves, or neurovascular coils, used to treat brain aneurysm).
 
As mentioned earlier, original nitinol inclusions are distributed throughout the volume of material. Therefore, a negative test result of raw material does not mean that finished product surfaces are free of inclusions. During production operations mechanical, chemical, or electrochemical processes remove excess material and original inclusions could be revealed from the interior of material. Also during this time, foreign inclusions could be introduced to finished surfaces by manufacturing processes such as laser cutting and sand blasting.
 
Experts in the nitinol field generally agree that electropolishing is the gold standard of finishing processes for nitinol implants. Electropolished nitinol implants have shown superior results in research compared with implants finished by other processes in terms of corrosion resistance, biocompatibility, reduced nickel leaching, and fatigue resistance, except for magnetoelectropolishing.
 

Figure 6. XPS data showing the compounds of electropolished (EP) nitinol wire surfaces exposed to 6% solution of sodium hypochlorite (NaClO) for 24 hours (EP+NaClO) and magnetoelectropolished (MEP) nitinol wire surfaces exposed to 6% solution of NaClO for 24 hours (MEP+NaClO).

The question of whether the test can damage or mitigate the properties of electropolished or magnetoelectropolished inclusion-free nitinol surfaces has been raised, but such damage is unlikely. The XPS results (see Figure 6) comparing composition of surface oxides on electropolished and magnetoelectropolished inclusion-free nitinol before and after 24 hours exposure to 6% NaClO do not show chemical composition changes.
 

Conclusion

The proposed test for checking nitinol surfaces for inclusions presents the possibility to inspect each implantable nitinol device and increase its safety margin. Device OEMs may benefit from adopting a policy to test each single implantable device. Doing so could increase the safety of peripheral stent or heart valve recipients. The process could eliminate devices that show a high probability of fracture or jeopardized effectiveness through activating and speeding up of the restenosis process.
 

Acknowledgments

The author would like to thank professors Tadeusz Hryniewicz and Krzysztof Rokosz of Politechnika Koszalinska, Division of Surface Electrochemistry, Poland for providing XPS data.
 

References

1. B Thierry et al., “Nitinol versus Stainless Steel Stents: Acute Thrombogenicity Study in Ex Vivo Porcine Model,” Biomaterials 23 (2002): 2997–3005.
2. AW Hassel, “Surface Treatment of NiTi for Medical Application,” Minimally Invasive Therapy and Allied Technology 13, no. 4 (2004): 240–247.
3. R Rokicki et al., “Nitinol Surface Finishing by Magnetoelectropolishing,” Transaction of Institute of Metal Finishing 86, no. 5 (2008): 280–285.
4. XM Wang, YF Wang, and ZF Yue, “Finite Element Simulation of the Influence of TiC Inclusions on the Fatigue Behavior of NiTi Shape-Memory Alloys,” Metallurgical and Materials Transactions A 36, no. 10 (October, 2005): 2615–2620.
5. G Siekmeyer et al., “The Fatigue Behavior of Different Nitinol Stent Tubes Characterized by Micro Dog-Bone Testing,” Medical Device Material IV, Proceedings 7, from the Materials and Processes for Medical Devices Conference (2007): 88–93.
6. DE Allie et al., “Nitinol Stent Fractures in the SFA,” Endovascular Today (July/August 2004): 22–34.
7. LHG Franca et al., “Update on Vascular Endoprostheses (Stents): from Experimental Studies to Clinical Practice,” Jornal Vascular Brasileirovol 7, no. 4 Porto Alegre (December 2008): 351–363.
8. DW Norwich et al., “A Study of the Effect of Diameter on the Fatigue Properties of NiTi Wire,” Journals of Materials Engineering and Performance 18, no. 5–6 (2009): 558–562.
9. S Shabalovskaya et al., “Nitinol Surfaces for Implantation,” Journal of Materials Engineering and Performance 18, no. 5–6 (2009): 470–474.
10. CTA Moreira et al., “Corrosion Behavior of Equatomic NiTi SMA in Sodium Chloride Solution,” 17°CBECMat—Congresso Brasileiro de Cencia dos Materiais, Foz do Iquacu, PR Brasil (November 15, 2006).
11. S Shabalovskaya et al., “Recent Observations of Particulates in Nitinol,” Material Science and Engineering A (2008): 431–436.
12. A Toro et al., “Characterization of Non-Metallic Inclusions in Super Elastic NiTi Tubes,” Journal of Materials Engineering and Performance 18, no. 5–6 (2009): 448–458.
13. S Shabalovskaya et al., “The Effect of Surface Particulates on the Corrosion Resistance of Nitinol Wire,” Shape Memory Superelastic Conference Asilomar (2003): 399–408.

Ryszard Rokicki is president of Electrobright (Macungie, PA).

Biocompatibility Testing: Tips for Avoiding Pitfalls, Part 2

Intramuscular implantation assesses local tissue response to an implanted material for the ISO 10996-6 implantation test.

However, manufacturers are on their own when it comes to how best to fulfill the testing requirements. This article is a continuation of “Biocompatibility Testing: Tips for Avoiding Pitfalls, Part 1,” which appeared in the January 2010 issue of MD+DI. It discusses several more elements of biocompatibility testing and also explores how to avoid problems that may arise along the way.

Cytotoxicity Testing

Cytotoxicity testing may be considered the canary in the coal mine of biocompatibility testing. Three basic categories of testing are required for every medical device, no matter how simple it may be. These categories are cytotoxicity, sensitization, and irritation and intracutaneous reactivity. The latter two are animal tests, and consequently are more expensive and take longer to get results. Therefore, when testing novel materials, the cytotoxicity testing is typically performed first. This serves as a barometer as to how the rest of the testing is likely to proceed, and sponsors with questionable materials advance only after the results of cytotoxicity testing are known. Some material vendors may only perform cytotoxicity testing before claiming that their product is a medical-grade material. Manufacturers should insist on certificates (test reports) for any material they purchase that is claimed to be medical grade.


The purpose of cytotoxicity testing is to determine the biological reactivity of the mammalian cell lines following contact with the material or the extract of the material. Cells are grown on plates. Depending on the test being performed, the cells are either derived from the ovaries of Chinese hamsters or from fibroblasts of mice. Once the cells reach an appropriate confluency or density, the test article, or extract of the test article, is exposed to cell population. Following the exposure, there is a period in which the plates will be observed for apparent cell death.


Cells are very sensitive and can be killed by minor changes in pH, salinity, or temperature. It is possible to have some incidence of this type of cell death, and this does not classify the test article as cytotoxic. But if the vast majority of the cells are dead or dying, the test article will be classified as cytotoxic.

Both in vitro and in vivo tests are required as part of a testing battery.


Sensitization

Sensitization testing establishes the potential of the test article to elicit an allergenic response. In particular, the testing is aimed at a delayed-type hypersensitivity response. This is an immune response that takes a couple of days to develop. Poison ivy is a good example of a delayed-type hypersensitivity response.  


Two primary test methods are used for medical devices to satisfy the sensitization testing requirement. The first is the guinea pig maximization test (GPMT); the second is the closed patch test, also known as the Buehler. Due to the use of an adjuvant to stimulate the immune system, the GPMT has been considered the more sensitive test. The GPMT has intradermal injections in the beginning of the study and topical applications at the conclusion. The Buehler consists of all topical applications. Due to the intradermal injections in the GPMT, the requirements specify that the test article be a liquid, suspendable powder, or extract. The Buehler is better performed with surface contact devices as they are used, if possible, and chemicals.
 

The third commonly used sensitization test method is called the mouse local lymph node assay (LLNA). The LLNA is an acceptable test method, but device manufacturers have been using the guinea pig tests for decades and are satisfied with the results obtained using those methods. The LLNA, like any test, has its pros and cons. It is shorter in duration, uses animals of a lower phylum, and requires far less test material; those factors can be appealing. On the other hand, it generates radioactive waste and is not accurate in distinguishing a sensitization response from an irritation response, which increases the possibility of a false positive. In addition, because the animals are sacrificed to harvest the lymph nodes, there is no opportunity to rechallenge if a question arises.


When proceeding with any sensitization study, it is necessary to know the irritancy potential of the test article. As already mentioned, the LLNA may confuse irritancy with sensitization. In the two guinea pig tests, the animals are scored for sensitization by evaluating erythema and edema (redness and swelling). Coincidentally, redness and swelling are also indicators of irritation. So it may appear that the GPMT and the Buehler could give a false positive to an irritating test article. But these studies have safeguards to prevent this. They are designed with primary irritation animals that receive varying concentrations of the test article all on one day at the same time. Because the animals have not been exposed to the test article before this point, any redness or swelling is considered an irritation response and not an allergenic response. These results are then considered when preparing the dosing solutions for the main part of the study. At the challenge dose, which is the final determining dosing, the animals are dosed at the highest concentration determined to not produce any irritation; any observation noted will be considered an allergenic response.


Irritation

Irritation testing determines whether the test article will cause irritation to the appropriate tissue. Various models are available to test an article. The most common model is referred to as the intracutaneous reactivity study (IC). In this test, extracts are typically used to inject five 0.2-ml boluses per extract into the skin of rabbits. The injections are usually the size of a mosquito bite. The skin sample area is observed every 24 hours for 72 hours following the injections and is scored for erythema and edema. The test sites are compared with control sites, and in order for the test article to pass, the difference of the average scores cannot exceed 1. The IC test can also be used with the test article directly if it is small enough to pass through a needle.


Other irritation models involve ocular, mucosal (oral, penile, bladder, rectal, and vaginal), and dermal tissues. The irritation test should use the most appropriate tissue for that device. For example, if the product is a contact lens case, then ocular irritation should be performed. A vaginal speculum should use a vaginal irritation study.


Even if appropriate tissue irritation is being performed, such as the ocular irritation in the instance of the contact lens case, consideration should be given to performing an IC test as well. On a topical dermal study, the test article is in contact with the epidermis. The epidermis is the first line of defense to protect us from the environment, and it has evolved to be fairly effective for that purpose. Therefore, some materials may not be detected as irritants by a topical dermal exposure, even if that is the most likely route of human exposure. Oral, rectal, vaginal, penile, bladder, and ocular tissues all have the ability to expel the test article or extract. The oral irritation study can utilize hamsters fitted with retaining collars to prevent a solid test article from being expelled. With the IC, the test article or extract is embedded within the dermis, and provides another evaluation as to the potential irritancy of the test article.

Shown here are mouse fibroblast L929 cells in culture for the ISO 10993-5 cytotoxicity assay.


Systemic Toxicity

In discussing systemic toxicity, one must first understand that the term systemic refers to the way the animal is affected as whole. In systemic toxicity testing, the animal is exposed to the test article or the extract of the test article. Four categories of systemic toxicity testing exist, and each is broken up by duration. The first is called acute systemic toxicity. This is a single exposure with typically a 72-hour observation. The next category is called subacute, which is a misnomer. In subacute toxicity testing, the animals are exposed to the test article or extract for 14–28 days.


Subchronic toxicity testing is a 28–90-day exposure, and chronic toxicity testing is a 6–12-month exposure. In the toxicity studies discussed in this section, the shorter duration is indicated when the test is conducted using an intravenous administration. The longer duration is for all other routes of administration. The category of testing required should be similar to the clinical exposure. Most medical devices will not need to pursue chronic toxicity testing. As the exposure period increases, so does the number of animals required. In these continuous or repeat dose studies, the animals are necropsied at the end of the study, and pathological evaluation is performed on the organs of the animals. In addition, chemical, coagulation, and hematological evaluations are performed on the blood.


The fourth type of testing that falls under the systemic toxicity category is called pyrogenicity testing. It assesses whether or not a test article has the ability to cause a feverlike response. In the United States, there are currently two types of tests for pyrogenicity, one is in vitro and the other is in vivo. The human monocyte test has been approved in Europe as an alternative to the rabbit pyrogen test. The in vitro test, known as either the bacterial endotoxin test or Limulus amebocyte lysate (LAL), only detects pyrogens that are bacterial in origin, called endotoxins. The in vivo test is called the rabbit pyrogenicity test; this detects bacterial endotoxins as well as material-mediated pyrogens. Therefore, the rabbit pyrogenicity test is required during the initial evaluation of the product, and the bacterial endotoxin test is used as a surveillance tool for bacterial con-tamination during manufacturing.


LAL uses a component of the blood of horseshoe crabs. In the presence of endotoxins, a component in bacterial cell walls, the LAL will clot. Using standard curves, the amount of endotoxin present is quantifiable. The rabbit pyrogenicity test involves monitoring the temperatures of rabbits for three hours following an intravenous injection of the test article or the saline extract of the test article. If any rabbit’s temperature increases half a degree Celsius following the injection, the test is considered positive.

Pyrogenicity testing is not to be confused with sterility testing. In the sterilization process, the bacteria on a material are killed but not removed. When the body is exposed to these dead bacterial components, it recognizes the presence of bacteria and responds with a fever as if there were an active infection. So just because something is sterile doesn’t necessarily mean it is nonpyrogenic.


Genotoxicity

Genotoxicity testing evaluates the test article’s ability to cause damage to DNA, genes, and chromosomes. Because of this, genotoxicity testing is performed as a battery. Genotoxicity testing typically consists of the bacterial reverse mutation assay, also known as the Ames assay, the mouse micronucleus test, and the mouse lymphoma or chromosomal aberration test.


The Ames assay uses bacteria that have been mutated to require specific amino acids in order to survive. The bacteria are exposed to the test article in the presence of just enough of these essential amino acids to allow for a limited number of replications. A proliferation of bacteria’s DNA indicates that the bacteria reverse mutated back to wild type bacteria and that these limited amino acids were no longer essential to survive.


The mouse micronucleus test is an in vivo test in which mice are exposed to the test article or extract. Bone marrow is harvested from the animals and is evaluated for the presence of micronuclei. Micronuclei are comprised of chromosomes or fragments of chromosomes and are indicative of chromosomal damage.


The mouse lymphoma test uses a mutated mouse cancer cell line in which a partially damaged gene exists. When this gene is completely damaged, this mutated cell line is able to survive and replicate in the presence of a particular chemical. The cells are incubated within that chemical after exposure to the test article. If an increase in viability is detected, this indicates the test article was able to totally inactivate or damage the gene.


The chromosomal aberration study typically uses cells derived from Chinese hamster ovaries (CHO cells). These cells are encouraged to undergo mitosis, or cell division. They are then exposed to the test article and a chemical that stops the mitosis in metaphase stage of mitosis. This is the stage in which all chromosomes are visible. At least 200 metaphase cells will be evaluated for visible damage to the chromosomes.


Genotoxicity testing is a crucial parameter of this area of  testing. It is required for anything that will come in contact with the body for over 30 days and anything that enters the body for more than 24 hours. Genotoxicity testing is important because, if something can cause genetic damage in these tests, it has the possibility to cause cancer.


Implantation

In implantation testing, the test material is placed into the body of test animals. Various species can be used for the implant test, ranging from mice to swine. The most typical animal used is the rabbit. Due to the size of the rabbit and the quantity of sites required to fulfill the guidelines, the rabbit is the most suitable model. Switching to rats is likely to increase the number of animals required to obtain the minimum amount of sites. Using more animals increases the cost.


The tissue chosen for implantation should be tissue that is most suitable for the test article. When in doubt, perform a muscle implant test. One benefit is that with the muscle implant, the test article is contained in a well-vascularized tissue, and this affords the body the maximum opportunity to react with the test article. For instance, a vascular shunt should be tested with a muscle implant test. In actual use, this device will be sutured into a vessel. Logic dictates that that test article be placed in an appropriate vessel in an animal, but this process should be for efficacy testing, not biocompatibility testing.


By using this device in the same manner as clinical use, the animal will need to be treated the same as potential patients. Anticoagulants and antibiotics will be administered to the animals, just as they would be with patients. Also, the surgical process is severe—sutures are introduced, cautery is used, and trauma as a result of clamping is created during the procedure. These variables prevent getting a true profile of how a body may react to this material. The best way to capture a potential reaction is to place small pieces of the test material into discrete pockets in the muscle along the spine of rabbits. That particular location is a single muscle mass, so there is minimal movement of the material after implantation.


Other sites for implantation would be into the subcutaneous space; bone, ocular, dental, or mucosal sites; or into the brain. If one of these locations is more appropriate for the finished test article, then that would be the better choice; otherwise use a muscle implant for your biocompatibility evaluations.


The duration of these implant studies is dictated by the clinical exposure time of the test article. Multiple time points will need to be conducted. For a permanent implant, a minimum short term of 1–4 weeks should be performed and a long term of over 12 weeks. Also consider doing a midterm of about 8 weeks. The point is to establish a steady state of the test site. In other words, if something from the test article was leaching out, it would be noticed in the short-term implant, but may have healed by 13 weeks. Or if something took a while to start leaching or degrading, nothing may be observable in the 1–4-week time point, but it will be evident at 13 weeks. Particular consideration should be given to the time point selection when testing resorbable or biodegradable materials. These selections should be based on the degradation rate of the test material.


At the end of the study, the implanted sites are retrieved and processed histopathologically. A pathologist evaluates the sites and scores them for a local tissue reaction. The scores from the control sites, which will be implanted with a proven biocompatible material, are subtracted from the scores of the test sites. This final score then categorizes the test material into a gradation of irritancy.


Hemocompatibility

Hemocompatibility testing includes a full battery of tests required of anything that comes into contact with blood. ISO 10993-4 clearly defines the categories of evaluations to be performed, as well as which types of medical devices need to have which tests performed. The five categories of hemocompatibility testing are thrombosis, coagulation, platelets, hematology, and complement system. With the exception of thrombosis, all of these tests are in vitro assays.  


In the thrombosis study, the test article is implanted into the vasculature of an animal. After a given period of time, the implanted vessel is removed and the test article is observed for clot formations.


The four remaining tests are carried out in test tubes and evaluate specific actions: whether or not the test article has an effect on the blood’s ability to clot or coagulate, can  regulate an immune response, or can damage the cellular components of the blood.


Supplemental Testing

Supplemental testing involves chronic toxicity testing and reproductive toxicity testing, as well as carcinogenicity studies and degradation studies. These are all long tests with high price tags. If such testing is required, consult qualified individuals to assist; a board-certified toxicologist or other professional with the proper education, training, and experience would be invaluable. These supplemental studies are not as cut and dried as the tests discussed earlier in this article. It’s advantageous to consult with someone who can put together appropriate testing for the product.


Conclusion

Medical device biocompatibility testing is filled with potential pitfalls in areas such as genotoxicity, irritation, and implantation. Because these pitfalls could delay a product launch, manufacturers must follow strict testing protocol and begin the testing process early enough to allow for thorough and complete testing. Manufacturers should also be as up to date as possible on all requirements, and they should consult other qualified professionals to provide expertise.


Bibliography

“Biological Evaluation of Medical Devices,” ISO 10993, parts 1–12 (Geneva: International Organization for Standardization, various dates).
“Use of International Standard ISO 10993, Biological Evaluation of Medical Devices—Part 1: Evaluation and Testing” G95-1 (Rockville, MD: Department of Health and Human Services, FDA, 1995).
“Testing Methods to Evaluate Biological Safety of Medical Devices, Notice from the Office Medical Devices Evaluation Number 36” (Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare, March 19, 2003).
“<87>Biological Reactivity Tests In Vivo.” United States Pharmacopoeia, most recent version.
“<88>Biological Reactivity Tests In Vitro.” United States Pharmacopoeia, most recent version.
“<1031> The Biocompatibility of Materials Used in Drug Containers, Medical Devices and Implants.” United States Pharmacopoeia, most recent version.
“Standard Practice for Selecting Generic Biological Test Methods for Materials and Devices.” ASTM F748-06.

Laurence Lister is director of biocompatibility services at Toxikon Corp. (Bedford, MA). 

Boost Your Bottom Line With Trade Terms

Although device company executives may dream of developing the next pacemaker, the reality is that most successful products are more modest than one of the industry’s most significant medical breakthroughs. When looking at a device manufacturer’s financial well-being, it’s important to keep this perspective in mind, because in much the same way, companies typically make their important business gains in small increments. This consistent approach contributes to both strength and stability over time. Managing cash flow is one such tried-and-true method.

Cash flow management is a game of balance and one that is often won in steady, consistent steps. Although there are sophisticated strategies and approaches to managing cash flow, every company can benefit from a solid understanding of some basic financial tools. Trade terms are one of the most useful of these tools.
 
A true classic in the cash flow toolbox, trade terms already help many small business owners. However, just as many small business owners fail to take advantage of them. Some proprietors may feel significant trade term benefits are out of their reach, while others may not understand how helpful they really are for improving liquidity. So, to help you maintain healthy cash flow, keep the following basics and tips in mind in order to put trade terms to work for your device business.

Trade Term Essentials

Most business owners know trade terms by a number of names. These include “supplier terms,” “trade credit,” “net terms,” “purchase terms,” “payment terms,” or simply “terms.” Regardless of what they’re called, the basic idea behind trade terms is the same: A company and its suppliers agree on the timing of payments and how much is due at a given date. Common agreements are “net 30” or “net 60,” meaning that a company must pay its supplier in full either 30 or 60 days from the invoice date. To encourage early payment, however, suppliers may include an incentive of 1% or 2% for customers who pay within 10 days.
 
When your business has cash and can make early payments, earning a 1% or 2% discount is a great option that puts your cash to work. While the early-pay discount may seem insubstantial, a consistent discount over a year’s time adds up to considerable savings. In a slow economy when profits are slim, discounts like this are a valuable tool for boosting margins. If your business earns a margin of 10% on a particular component, then the additional 1% received from the component supplier for early payment essentially widens your margin to 11%.
 
There are, of course, times when an early payment isn’t an option. To help customers avoid a cash-flow crunch, some vendors offer trade terms that will permit you to delay payment. Under these terms, customers agree to make a designated partial payment and are permitted to take the goods and defer full payment for a specified term such as an additional 30 days.
 

Pursue Better Terms

Whether you’re in a position to earn a discount or you need to defer payment, trade terms are a useful tool. The first step to gaining better terms is to recognize that not all vendors offer them, and for those who do, they’re not automatic. Companies are selective about who receives trade terms because they don’t want to take the risk of offering a discount to customers who will simply take the discount and then pay late. Likewise, they are cautious when extending deferment options, because doing so amounts to financing free short-term credit for customers.
 
Since trade terms are offered only in limited situations, receiving this privilege often requires the customer to make the first move. Approach your vendors with the goal of negotiating more favorable terms, keeping in mind that it may take time to earn the privilege. Because trade terms are about trust and creditworthiness, you can expect the most from companies with which you have the longest and best relationships. The better your track record overall and the better a company knows your business, the more likely you are to be rewarded with more favorable terms.
 
In cases where you haven’t been successful in negotiating trade terms, consider ways in which you can make your business more attractive to vendors. In addition to a good credit record and a healthy vendor relationship, other factors can tip the balance in your favor. Consider the things that make your best clients valuable to you, and use that knowledge to make yourself a better customer. The volume of business a customer provides, for example, is a significant factor in a customer relationship. With this in mind, perhaps you can consolidate your business for a particular type of goods or service with a single vendor. Another factor that affects how vendors see you is the regularity of your business. Look at your ordering patterns and decide whether you might formalize a standing order with a particular vendor instead of sending orders on an irregular basis.
 
There will always be vendors who don’t offer trade terms, or situations where you won’t be offered special terms. Furthermore, there are simply many kinds of expenses that will never qualify, such as utilities and phone bills. In these cases, look for other ways that you can improve cash flow by delaying payments while still meeting your financial obligations. Also look for alternative ways of earning discounts wherever possible.
 
Using charge and credit cards is one way to delay payment while still making sure suppliers are paid in a timely manner. Some also present the possibility of earning a type of discount in the form of cash back or other rewards. Another alternative that can improve cash flow is to use cards that offer trade-like terms.
 
There are more ways to improve cash flow, such as finding cash-free alternative payment methods beyond simply using credit or charge cards. For example, if you’re using credit and charge cards, make sure you’re actually using the rewards you earn to your best advantage.
 

Mind Your Credit, Manage Growth

Whether you already receive trade terms or hope to qualify for them in the future, it is important to establish—and keep—a strong credit record. Doing so will help you keep the terms you may already have and can help you earn more favorable terms later. If you’ve worked hard to build a strong credit record, then don’t keep it to yourself. Make it easy for vendors and credit issuers to confirm that you’re an established business. You can do so by registering with commercial credit bureaus like Dun & Bradstreet and the Small Business Financial Exchange.
 
You’ll also want to make certain that the credit records on file are up-to-date and accurate. Contact credit bureaus to verify the information in your credit report and check your company profile for errors. If you do find mistakes or irregularities, be sure to address them immediately to maintain good standing.
 
There are few downsides to growth, but one undesirable outcome is that unmanaged growth can take a real toll on cash flow. To keep cash flow even, manage growth whenever possible to keep it consistent and even, avoiding sudden and dramatic leaps. When growth opportunities arise, plan carefully with an eye on cash-flow projections. And each time you invest in growth opportunities, stick to the essentials: Every investment, whether in materials, labor, or equipment, should have a clear return. Make sure each will earn a profit, and look at how long it will take to collect that profit. Additionally, make a conscious decision about how much you have to spend in order to reach your goal and how long it will be before you pay back any associated debt. Likewise, if you look at each customer as an investment with a scheduled return, you’ll not only improve cash flow but your profitability as well.
 
Since debt is usually necessary in times of growth, make sure you have a plan in place for when cash is needed to take advantage of opportunities. Likewise, it’s important to have a backup plan for short periods where you simply need to cover a temporary cash shortage. To cover both situations, be certain your company is prepared with several sources of financing in advance. One of the reasons it pays to plan ahead is that some financial institutions may be more likely to extend lines of credit or loans when your company is in good financial health, and less likely when cash flow problems have already taken a toll on your finances.
 
When seeking financing, be sure to explore whether your business may quality for special lending programs, such as those designed to assist small businesses owned by women or minorities. Once you have credit available to you, use it as it was intended for short-term financing options such as lines of credit, short-term loans, or credit cards toward short-term cash needs. Likewise, use long-term or secured loans for the purchase of long-term investments.
 
In today’s slow economy, managing cash flow may sometimes seem to be more about maintaining an even keel than preparing for significant growth, as nearly every company faces later payments from customers. But the cash flow lessons learned today are about more than steady-as-she-goes. Those companies that develop the slow and steady discipline of cash flow management will have the tools to take on new challenges and growth opportunities when an economic recovery does eventually come.
 
Richard Flynn is senior vice president and general manager for American Express OPEN, an issuer of card products for small business owners. For further information contact [email protected].

Web Site Directory

Ark-Plas Products Inc.
 
Hardware and Accessories
Lyons
 
Manufacturing Equipment and Software
EtQ Inc.
 
Materials
Proto Labs Inc.
 
Packaging Equipment and Supplies
Dymax Corp.
 
Pumps and Valves
Gems Medical Sciences
 
R&D, Design, and Business Services
Gems Medical Sciences
GlobTek Inc.
Lyons
Minnetronix
Okay Industries
Phillips Plastics Corp.
Proto Labs Inc.
R&D/Leverage
 
Tubing
Ark-Plas Products Inc.
Vesta Inc.
 
 
COMPANY LISTINGS
 

Ark-Plas Products Inc.
165 Industry Ln.
Flippin, AR, 72634
Ark-Plas Products Inc. manufactures more than 5000 products in the United States including plastic fittings, tubing, and accessories. The company also makes check valves, filters, stopcocks, decorative screw covers, and quick bind hardware. Featuring in-house tooling design and manufacturing, the ISO 9001:2000­–certified manufacturer has custom molding capabilities.
 
Dymax Corp.
318 Industrial Ln.
Torrington, CT 06790
Dymax’s Web site offers information on light-curable adhesives and light-curing equipment for medical device assembly. It features adhesives for bonding reservoirs, syringes, respiratory masks, catheters, optics, and surgical instruments. Users can download product guides, white papers, PDS, biocompatibility reports, MSDS, technology guides, and PR. They can also order samples, get quotes, request technical assistance, and view webinars and videos. http://www.dymax.com/products/medical/index.php
 
EtQ Inc.
399 Conklin St., Ste. 208
Farmingdale, NY 11735
EtQ’s FDA compliance management software is designed specifically to help the medical device industry maintain compliance to various regulatory requirements and adapt to business processes. EtQ’s modules are tightly integrated to deliver such FDA-compliance functions as corrective and preventive action, document control, change management, and risk assessment.
 
Gems Medical Sciences
1 Cowles Rd.
Plainville, CT 06062
Gems Medical Sciences provides fluid handling expertise, components, subassemblies, and systems for medical equipment manufacturers. Its capabilities include engineering design, product development, rapid prototyping, and manufacturing services.
 
GlobTek Inc.
186 Veterans Dr.
Northvale, NJ 07647
GlobTek Inc. designs and manufactures stock, modified, and custom wall plug-in power supplies, as well as desktop and open-frame supplies. Class I and II input configurations are available in 90–264 V ac at 47–63 Hz. Outputs can be up to 2000 W in 3.3–48-V increments. The company provides protection for overcurrent, short circuit, overvoltage, and overtemperature and is certified to international regulatory requirements. All products comply with the EMC Directive as well as CE, FCC, and VCCI requirements. The company is ISO 9001:2000 certified.
 
Lyons
185 Research Pky.
Meriden, CT 06450
Lyons specializes in rapid prototyping (metal stampings, assemblies, surgical knives and scissors, machined components, and medical devices), progressive dies, precision grinding, assembly fixtures, and contract manufacturing. The company also offers product design assistance, program management, packaging, and cleanroom assembly. It is ISO 9001:2000 certified and FDA registered.
 
Master Bond Inc.
154 Hobart St.
Hackensack, NJ 07601
Master Bond Inc. is a manufacturer of bonding, sealing, and coating compounds for advanced medical devices. These materials meet USP Class VI requirements and are packaged for easy, efficient application. Master Bond offers a wide selection of high-quality formulations. The company also provides technical expertise and can help in solving specific problems. The company’s products are only sold direct.
 
Minnetronix
1635 Energy Park Dr.
St. Paul, MN 55108
Minnetronix is a medical device outsourcing company specializing in the design, manufacture, and support of electronic-based medical devices. The company’s team provides expertise on equipment such as cardiovascular systems, point-of-care diagnostic instruments, therapeutic devices, implantable devices, and monitoring equipment. The company is ISO 13485:2003 certified and is an FDA-registered contract manufacturer.
 
Okay Industries
200 Ellis St., P.O. Box 2470
New Britain, CT 06050
Okay Industries specializes in complex metal stamping, CNC machining, automated mechanical and welded assembly (including laser), and surgical blades and scissors using the company’s Accu-Blade technology. R&D, product development with concurrent design and build, prototyping, and rapid tooling services are also provided. The manufacturer assists companies from concept through production.
 
Phillips Plastics Corp.
1201 Hanley Rd.
Hudson, WI 54016
Phillips Plastics has four FDA-registered facilities with more than 150,000 sq ft dedicated to medical manufacturing services. The company can design for multiple molding processes and bring the manufacturing perspective to the concept phase.
 
Proto Labs Inc.
5540 Pioneer Creek Dr.
Maple Plain, MN 55359
Proto Labs, through its first cut and protomold services, uses proprietary computing technologies and automated manufacturing systems to provide prototype parts and short-run production services. All parts are made by standard production methods and can be delivered in one day.
 
R&D/Leverage
1009 SE Browning Ave.
Lee’s Summit, MO 64081
R&D—Integrated Solutions in Plastics is a full-service plastics product provider. Its packaging design component, Leverage—Integrated Industrial Design, is located in a separate facility on R&D’s campus. Leverage’s range of services include up-front research, concept development (story boards, feasibility studies, digital prototyping, graphic design, and branding), validation (online design and model making) and implementation (prototype molds, mold sampling, and low-volume production).
 
Vesta Inc.
5400 W. Franklin Dr.
Franklin, WI 53132
Vesta is a global manufacturing and support services company for the OEM medical device industry, providing silicone moldings, precision silicone and thermoplastic extruded tubing, assemblies, and secondary operations within ISO-certified facilities. The company has expertise in quality standards, product design, and material selection.