Several materials are known to show signs of toxicity in certain biocompatibility tests but are still safe to use. The best examples are latex and nitrile. Latex is the positive control for the cytotoxicity test, and nitrile gloves fail the hemolysis test, yet these materials are still acceptable medical device materials. The first thing you must do is show that the known problem material is not ‘hiding’ other toxic components. This is done by removing the problem material from the test in which it is known to show a positive result. Then, you can evaluate the other materials and processes to determine that the results are being derived from that one problem material only. After that, you can use either an industry search or expert opinions to justify the acceptance of the failure.

We would do agar overlay for cytotoxicity, skin sensitization, and primary skin testing, and that’s all.

We have not had any issues with the FDA for any of the batch-release testing we have performed for any of our sponsors. Although we base our testing on TIR16, our testing is also based on ISO 11135. As the contractor, we do it all the time.

One reason why the adhesive might stick better to the foamed PE is its larger surface. Adhesives in general can hold on better and achieve a mechanical lock when holes and grooves are present. According to the supplier’s Web site, the primer you are using is recommended for PE. If it is not providing the desired results, you may want to look into other surface treatment methods such as plasma or corona, which add polar groups to the surface and usually result in higher bond strengths.

On your first question, the major difference in this new edition of ISO 10993-1 is the incorporation of a risk management process as part of the overall biological evaluation and development of each device. This approach combines the review and evaluation of existing data from all sources with, where necessary, the selection and application of additional tests, thus enabling a full evaluation to be made of the biological responses to each medical device that are relevant to its safety in use.

On your second question, the justification for not performing biocompatibility testing would involve a rationale that compares the device or materials with similar products that are already on the market and have undergone favorable biocompatibility testing or involve favorable historical use data. However, the processing of the materials into the final device and the interactions of the materials with other materials in the device would have to be addressed as well.

Material characterization is addressed in the ISO standards and can be performed at different levels. As indicated in ISO 10993-1, “The extent of chemical characterization required depends on what pre-clinical and clinical safety and toxicological data exist, and on the nature of the body contact with the medical devices.” It also states, “If the combination of all materials, chemicals and processes has an established history of safe use in the intended application, then further characterization and biological evaluation might not be necessary.”

Figure 1 in the ISO 10993-1 guidelines gives a summary of the systematic approach to a biological evaluation of medical devices as part of a risk management process. It includes steps such as obtaining device material identification and chemical characterization (ISO 10993-18), comparing the material with a known commercially available device, comparing the chemical composition with the known commercially approved device, etc.

For devices that have the same or very similar materials compared with known materials with favorable biocompatibility results, the material characterization testing can be performed using chemistry tests that look for nonvolatiles, volatiles, or semivolatiles using mass spectrophotometry (ICP-MS). This testing can be done for the new materials for approximately $2000 to $3,000, and the turnaround time is approximately 14 to 17 days. ICP-MS testing can also be conducted for test articles with metals.

Recommended for single-use medical devices made of polyurethane, PVC, polycarbonate, and many other plastics, Dymax’s 204-CTH-F light-curing adhesive is a possibility. It enables the bond to fluoresce blue under black light for quality purposes and features flexibility that makes it suitable for assembling rigid and flexible components.

On the other hand, because it is difficult to adhere polyurethane to latex, 204-CTH-F may not provide the desired bond strength. Typically, a cyanoacrylate such as Dymax’s 222 series can be used for bonding with latex, but it does not provide a flexible bond.

If you want to be able to see the adhesive while you dispense it and confirm the quality of the cure, I would suggest that you try either Dymax’s 1201-M-SC or 211-CTH-SC adhesives. Both are light-curable adhesives equipped with See-Cure color-changing technology, which makes the adhesives appear blue in the uncured stage. When fully cured, they become colorless, ensuring that the curing process is complete.

On occasion, full cure via UV/visible light can be achieved using opaque polypropylene hubs. Depending on the color and thickness of the polypropylene, some light from the side can transmit through the plastic and polymerize the UV/visible adhesive.

The largest portion of the adhesive is usually cured from the top. However, due to limitations in the depth of cure of most UV/visible adhesives, I would recommend keeping the length/depth of the bond joint to a minimum and molding the annular rings near the top of the hub. Suitable UV/visible light–curable products include Dymax 1180-M-SV04 and 1-20777, which are medium viscosity and will not flow deep into the hub. Low-viscosity products such as Dymax 1161-M or 1162-M can be used if the design of the bond joint prevents these materials from flowing too deeply into the hub.

In order to achieve short curing times, I would recommend using a high-intensity UV lamp such as Fusion F300, which is a focused-beam lamp, or Dymax Blue Wave 200, which is a spot lamp that can be equipped with multiwand light guides.

There are 4 types of cyanoacrylates. Two of them can be used for closing wounds and are available from different suppliers:

1. Butyl cyanoacrylate is used to bond skin and close wounds. Available from Henkel (Indermil), Advanced Medical Solutions Group (LiquiBand), and B. Braun (Histoacryl), all versions are FDA approved.

2. Octyl cyanoacrylate is a newer-generation glue for bonding skin and closing wounds. It is supposed to provide higher breaking strength and be less irritating to skin than the butyl-type adhesive. Available from Adhezion Biomedical (SurgiSeal), Ethicon (Dermabond), and Chemens Medical Products (derma+flex QS), all products are FDA approved.

3. Ethyl cyanoacrylate is the most commonly used adhesive for assembly purposes.

4. Methyl cyanoacrylate is used for assembly purposes.

Layer stacking parts on rice paper may be the best scenario to reduce sticking and keep the parts from contacting each other. Also, making sure you are postcuring the product after molding can ensure that the product is fully cured and, perhaps, slightly less tacky. A mat finish in the tool may also cause less coining or sticking between parts.

There are lots of good data on nitinol biocompatibility. Every medical implant commercialized in the United States is subjected to some, if not all, of the tests required by ISO 10993—the biological evaluation of medical implants. However, these tests are unique to specific designs and surface finishes and are generally proprietary.

There are also quite a bit of published data in the literature. For example, a PubMed search on nitinol biocompatibility yields 81 publications, and there are also a few biocompatibility-related publications available on the NDC Web site.