Blog

Concerned about the dire shortage of personal protective equipment in Massachusetts hospitals, Cambridge Polymer staff searched our lab supplies for possible contributions. CPG donated disposable lab coats, shoe covers, hair nets, isolation gowns, surgical masks, nitrile gloves, face shields, goggles and safety glasses through the Massachusetts Emergency Management Agency. 

The PPE-gathering staff member who received CPG's donation was so grateful that initially he wanted to shake hands. We settled for a socially-distant wave.

Released this January, the new revision of ISO 10993-18 dramatically expands the scope of determining biocompatibility of medical devices by an additional 49 pages over the previous revision. The standard’s new title “Chemical Characterization of Medical Device Materials within a Risk Management Process” emphasizes the importance this revision places on risk assessment. The chemical risk assessment workflow may be viewed as a three-tiered structure composed of: 1) information gathering 2) extractables analysis, and 3) leachables analysis. The need to perform each successive tier of characterization depends on the nature of the device and the results of the previous stage.

Chemical Risk Assessment Workflow

Made explicit in ISO 10993-18:2020, the critical first step of the chemical risk assessment is information gathering. This involves collecting all available data on the medical device’s materials of construction, additive packages, surface treatments/coatings, etc. In addition to information on the compositional level, the information gathering step also includes collection of the manufacturing processing aids and processing conditions: e.g. machine oils, spin finishes, polishing compounds, sterilization modes, etc.

For devices of greater risk or more uncertainty in materials/manufacturing, an extractables study is likely to be required, at minimum. If an extractables study finds chemicals presenting a potential toxicological risk, a targeted leachable study may be necessary to evaluate the actual concentration of the compound when the device is subjected to simulated end-use conditions.

We have all experienced the challenges of keeping a bandage on a wound when the skin becomes wet from sweat, water, or blood. Traditional bandages rely on adhesion between a portion of the bandage and the skin. This adhesive bond is compromised when water or other fluids penetrate between the layer.

Hydrogels have been examined in the past as a potential alternative to traditional bandages. Hydrogels, which are three dimensional networks of a hydrophilic polymer that is crosslinked to prevent dissolution, can be designed to have adhesive qualities even in the presence of water.

Researchers at Harvard University are experimenting with two naturally occurring hydrogels (alginate, from seaweed, and chitosan, from the shells of crustaceans) to make a hydrogel bandage that looks like a patch. The hydrogels also incorporate a thermo-responsive polymer (NiPAAM) so that the patch shrinks upon skin exposure, bringing the edges of the wounds together. Early studies on mice show that wound closure is significantly faster than traditional bandages or hydrogels lacking the thermo-responsive polymers.

Figure 1: Chinese woodprints of the papermaking process (Wikimedia Commons)

Cellulose is one of the most abundant organic compounds on earth and utilized in applications as diverse as textiles, papermaking, food packaging, filtration, drug delivery systems, wound care products, nanocomposites, bone tissue engineering, and countless others. Cellulose is a fibrilar and semi-crystalline biopolymer which may be plant-derived or bacterial-derived, and generally exhibits remarkable mechanical properties as well as desirable biodegradability, biocompatibility, renewability, chemical stability, and cost effectiveness.  [1]

Cellulose is notoriously difficult to process. Up until approximately 300 million years ago, there were no significant microorganisms capable of digesting cellulose—resulting in a high accumulation of organic matter. During this “carboniferous” period, the production of coal derived from biomass was 600 fold higher than estimated rates of production in modern day. [2]

Molecular Weight Analysis of Cellulose

As polymer and material scientists, we rely in fundamental measurements of polymer properties to understand the material performance in demanding circumstances. Typically, this includes measurement of the polymer molecular weight—however, this is a highly challenging measurement to obtain for un-modified cellulose materials. Simply put, cellulose doesn’t dissolve in most solvents as a consequence of its crystalline structure, hydrogen bonding, and hydrophobicity.

CPG has developed workflows for the molecular weight analysis of cellulose materials, including un-modified cellulose. Samples are carefully prepared in a series of matrix-modifying steps before ultimately  being dissolved in an aprotic solvent and in the presence of high inorganic salt concentrations. Once in solution, the cellulose materials are analyzed by triple detection GPC for absolute measurement of the polymer molecular weight as well as structural characterization. By obtaining such fundamental measurements of molecular weight and structure, cellulose products may be evaluated for (bio)degradation, aging, failure analysis, material compatibility, lot-to-lot consistency, among other properties. Contact CPG for additional information on the material characterization of cellulose or other biopolymers.

Do I have to do chemical characterization? 

Is it appropriate to perform extractables testing and chemical risk assessment on metallic components?

As such evaluations are most commonly associated with polymeric constructs, it may seem strange to evaluate a solid metallic component in this way.

ISO & FDA Medical Device Guidance

For clarity on this issue, we turn to ISO 10993-1:2018 and the FDA 2016 guidance on biocompatibility assessment. These documents emphasize that the first step in assessing a device's biocompatibility is in compiling a detailed understanding of the physical/chemical properties and chemical composition of the device. Only once this information is in hand can an evaluation and risk assessment be performed with regard to toxicological endpoints such as carcinogenicity, genotoxicity, etc.

Base Alloy vs. Surface Residue 

For a metallic device, the question of chemical composition may seem straightforward: is it simply the alloy the device is machined or otherwise manufactured from? Unfortunately, considering only the base alloy does not take into account the processing aids which are used in the manufacture of the device and which may be left behind as residues on the surface of the part. These may include polishing compounds, lubricants, machine oils, cleaning agents, or adhesive residue from tape used to 'mask off' regions of the device. Inorganic residues (particulates, ions, elemental impurities, etc) that may be released should also be considered separately from the base material. An additional factor to consider is if the component has highly porous regions (e.g. to facilitate osseointegration) which may make the device more difficult to clean and in which manufacturing residues may linger.

Chemical Risk Assessment or Cleanline Validation? 

In some regards, extractables and chemical risk assessment on metallic components blurs the line with the scope of work performed as part of a cleanliness assessment or clean-line validation - the workflows are in many ways similar and involve extracting the device in solvents of varied polarity and analysis of resultant extracts using techniques such as GC-MS, LC-MS, and ICP-MS. The results of this testing are a list of the identified organic and inorganic extractables which may then be inputs into a toxicological risk assessment. Often this process--other than being a key starting point of the ISO 10993-1 biocompatibility assessment-- may mitigate the need for more extensive (and expensive!) animal testing.

 Do I have to do chemical characterization?

Overheard at a recent conference: "Oh, our device isn't a permanent implant, so we don't need to do extractables testing."

Is that right? If a device is implanted for less than 30 days (or even less than 24 hours), is extractables and chemical characterization unnecessary?

For clarity on this issue, we turn to ISO 10993-1:2018 and the FDA 2016 guidance on biocompatibility assessment. Each of these references contains a table which breaks down the biocompatibility evaluation endpoints associated with different implantation durations and the nature of body contact. Even in the case of a "limited" contact duration of less than 24 hours, these documents indicate that a biocompatibility assessment be performed. What does that entail, however?

The first step in performing any extent of biocompatibility assessment is to compile a detailed understanding of the physical/chemical properties and chemical composition of the device. Only once this information is in hand can an evaluation and risk assessment be performed with regard to toxicological endpoints such as carcinogenicity, genotoxicity, etc. For short term implants, the number of biocompatibility evaluation endpoints is generally less extensive than long term implants.

If the chemical composition of the device (both the raw materials as well as any manufacturing residues) are unknown or have not been previously characterized, an extractables assessment is typically necessary to determine the composition. Unless the device manufacturer has previous experience characterizing the material/manufacturing process by extractables, sufficient information on the device composition (including impurities, manufacturing residues, etc) is generally not available for this to be a pure paper exercise.

Note that from an analytical perspective, given the short term nature of the device, the analytical evaluation threshold (AET) employed will be less stringent than for a permanent implant. This means that when evaluating extractables data from techniques like GC-MS, and LC-MS, the number of peaks which must be identified and submitted for toxicological risk assessment is significantly lower than for a permanent implant--translating to generally lower cost and faster turnarounds.

ISO 10993-1:2018 Table A.1