How are materials tested?

How are biomaterials tested prior to implantation?

Testing begins with a toxicological risk assessment, then in vitro testing, and then finally in vivo testing before it can then be implanted into the body.

Toxicological risk assessment:

Identify hazardous chemicals present in biomaterial.
Assess the patients potential exposure to these chemicals.
Determine the chemicals dose response relationship.
Combine information and results found and assess the risk.

Examples of standardized in vitro tests:

In vitro cytotoxicity
Interactions with blood
Interactions with degradable materials and leachable material
Genotoxicity (is the material going to induce mutations in DNA) and carcinogenesis (the tumorigenic potential).

Examples of in vivo tests:

Intra-cutaneous tests (to assess risk of allergic reaction)
Implantation
Biodegradation
Immunological
Systemic toxicity measured by fever test (systemic inflammation response)

{7}

[12] This image shows an intra-cutaneous test to assess if someone is allergic to subcutaneous heparin injections.

However, there are many challenges with these tests. Most of the time, these biomaterials are tested on animals which raises a lot of animal cruelty questions. Also we are designing devices for humans, yet we are testing them on animals. An animals response to a certain biomaterial could be good, but it could then be implanted into a human and cause many adverse effects. Many companies are now trying to adopt the 3-R principle:

Replace - Replace animal experiments with another method.
Reduce - Only have necessary animal experiments.
Refine - Minimize the stress and burden on the animals.

Why is testing important?

Testing is important as it can be difficult to predict what the biomaterials will do once inserted into the body.

Macrophages will bind to the surface of the biomaterial, and form a Foreign Body Giant Cell (FBGC), they will release proteins which degrade the material over time and can also cause degradation of the material via oxidative stress and degrading enzymes. This means that we need to test the material to make sure that it will not be damaged by the degrading enzymes.

Metallic materials will release oxides and hydroxides when they degrade in the body, and can be found in your circulation, lymph nodes and liver. If there are too many oxides, this can become dangerous and even fatal. This shows how important testing is as biomaterial degradation can have local and systemic biological effects.

Different materials give off different kinds of toxicity. There is chemical toxicity (metal ions, chlorine gas etc.), biological toxicity (bacteria or viruses etc.), and physical toxicity (asbestos, nitrogen gas etc.).

[13] This image shows how if not tested correctly, biomaterials have the potential to break in the body, and cause even more damage.

What adverse effects have been reported following biomaterial implantation?

Adverse effects:

Infection
Rejection
Degradation of metals
Blood clots, which can then cause a stroke or heart attack
Allergic reaction
Joint pain
Tumor formation

Example:

Titanium is now used for orthopedic surgical implants. But what was used before?

Before titanium was used, gold, silver, lead and aluminum were used. Gold is still used for implants, but mainly in dentistry. Lead is no longer used as it caused lead poisoning which over time becomes fatal. Aluminum is also not used as it is also toxic in high doses. Silver is not used anymore either as even though it is a great antibacterial agent, it too is toxic and can cause hemorrhaging, bone marrow suppression and even pulmonary edema.

Titanium is now used for surgical implants as it is very biocompatible and does not cause many adverse effects. It also does not corrode in the body like other metals would, and is very durable. Another advantage of titanium is that people with titanium implants can still have an MRI scan, which would not be possible with other metals. One complication is if the person getting the implant has an allergic reaction to titanium, however this is very rare and can be easily preventable with an allergy test.

{8}{9}

[14] The above photo shows an example of how titanium rods are used in orthopedic surgery, in the femur and tibia.