Depending on the usage/category of Biomaterials, like surface biomaterials, implants, they must undergo different types of testing which are set by ISO 10993 standards like cytotoxicity, genotoxicity, sensitization, chronic toxicity, carcinogenecity. For example, a surface biomaterial should be tested for its interaction with body tissues and also with external environment as specified by ISO standards. For an implant which stays in contact with body tissues forever it should be tested for its interaction with body tissues (biocompatibility) as set by ISO standards. Once the biomaterial is tested for all tests depending on the category, it can be used for clinical trials after getting approval.
The reason a biocompatibility test is performed is to determine the effectiveness and durability of a biomaterial, medical device or drug for human use and to analyze any potentially harmful or physiological side effects. To prevent insufficiently tested materials and devices from entering the market, governments around the world have established medical device regulatory organizations. One such body is the International Standards Organization (ISO). The ISO 10993 standard gives the basic guidelines for biocompatibility and its testing. Subdivisions of this standard specify which tests need to be performed for hazard identification on biomaterials and devices - these tests include genotoxicity, carcinogenicity and reproductive toxicity. Additionally, for pre-clinical research, the ISO 10993-2 standard identifies specific animal welfare requirements that need to be met for all animals used in animal tests to analyze the biocompatibility of biomaterials. The amount and type of compatibility tests performed would depend on if the biomaterial is to be implanted, use on the skin or surface, or if its part of a communication device. Regardless of where it is placed, there are three factors that all biomaterials are checked for - cytocompatibility evaluation, sensitization, and irritation or intracutaneous reactivity.
As the other before me have said, the biomedical device will have to comply with ISO 10993. This means that the medical device in question cannot harm a subject depending on the application. This can be viewed in the toxicity chart from this week's lecture. You'll have to narrow down your device into a category related to the body contact involved with the device (surface, external communicating, or implant). After that you'll have to further narrow down the type of device until you get to the point where you can see what biological effects you have to test for for your particular medical device. Typically, all devices will have to test for cytotoxicity, sensitization, and irritation or intracutaneous reactivity. Other tests may have to be performed for effects such as genotoxicity if the device is more invasive.
I agree with others about ISO10993.
I would also like to add a few points. Before a new biomaterial product is going into clinical practice, a few special considerations should be examined:
1. Product characterization: component-cellular, noncellular, combination ...
2. Product safety: toxicity (acute/chronic damage to cells, tissues..); physiological effects (effects on vital signs: blood pressure, heart rate); tumorigenicity (propensity to form tumors as a result of implant); infectious disease; adverse immune response;
3. Efficacy
4. Preservation (the ability to preserve cells and tissues).
5. Regulations
As mention, for testing in biocompatibility, the testing should follow ISO 10993. However, depending on the product there are various other testing that needs to be done before the procurement of any material that goes into a process and after the product is completed. This also have to go through the QC department, that will either do additional testing or confirm any testing done before is with in desired integrity. The company that I work with has a product that is a consumable that going into the body. For different product, I think that the testing would differ. I also think the process would also dictate also of the testing. Depending on how much sterility is needed for the process, there may be various testing done to, insure that the product can maintain its efficacy and not do any damage the biological system.
For orthopedics that go into the body also must be considered in the process that would insure the immune response is with in expectation. In most cases with orthopedic implants, the coating is what dictates how the biological system will respond. The is where testing for biocompatibility can focus in on. I think that this will differ depending on the product.
Biomaterials should be tested for biocompatibility in regards to ISO 10993 before any clinical trials. Biomaterials are classified into different categories based on their usage like surface biomaterials, implants etc. ISO 10993 has set standard tests for these Biomaterials according to their category. These tests shoe that how safe the biomaterial is for the surrounding body tissues. Biomaterials should not interact with the internal body tissues in case of implants and also in case of surface biomaterials they should not interact with external environment along with internal body tissues. Tests like genotoxicity, carcinogenicity, sensitization, cytoxicity, hemocompatility etc ensure the biomaterials biocompatibility.
In order to determine what biocompatibility testing a device needs, ISO 10993 can be referenced. There are various tests and requirements that need to be evaluated for each medical device based on its intended use and duration of use and location of use. The most broadly applied tests are cytotoxicity, sensitization, and irritation/intracutaneous reactivity; which are required for every investigational device. The table then identifies additional tests based on the nature of the device interaction with the human body. For specific organs, additional biocompatibility testing with cells from the designated area will need to be considered, as well as more thorough types of tests (carcinogenicity, acute and chronic toxicity, etc).
There are multiple biocompatibility tests that needs to be carried out on the product prior to clinical trials. These tests must comply with the ISO 10993-1, Biological evaluation of medical devices. As per the ISO 10993 standard, biocompatibility tests include cytotoxicity, sensitization, hemocompatibility, pyrogenicity, genotoxicity, and implantation. These tests will help determine if the device possess any foreign object or micro-organisms that can potentially harm the patient if implanted. A biomaterial or medical implant that is a sterile device and in contact with lymphatic system requires the pyrogenicity test. On the other hand, for biomaterial or medical devices having direct contact with circulating blood requires the hemocompatibility test. All in all, there are multiple tests for various applications that is required prior to clinical trials and all the test must comply to ISO 10993-1 and the applicable ASTM standard.
There are various types of biocompatibility tests depending on the type of therapy the material is involved in delivering. One of the most important is cytotoxicity test that goes hand-in-hand with hemocompatibility. Cytotoxicity tests check for sustenance and maintaining the health of all the tissues in the body post administration of the drug. It differs for different applications: for example as biomaterials in contact with the uterine tissue need to pass the uterine tissue biocompatibility tests and biomaterials in contact with the neural tissue and so on. However, for orthopedic implants, apart from biocompatibility and hemocompatibility tests, one has to test the structural strength of the implant as each implant is custom made according to the demographics of the patient. It is important to check the strength and stability of the orthopedic implant to ensure its long-term usefulness and effectiveness.
If I am working with a biomaterial that has never been used before, I shall do every single test that I can think of. Starting with all of the ISO 10993-1 standards. The reason being is the amount of liability that I will have if ANYTHING goes wrong that I had no idea would happen (but should have). When moving into uncharted territory, utilizing your best performance of duty is even more essential than normal. You want to get it right or as close to right as possible so that as you move forward, you will have a better idea of what's going on. I wouldn't stop at just the standards either. Other tests that I feel would be beneficial will be conducted as well. I would rather have a large pool of information to reference back to vs not having enough data.
If a company were to develop a new biomaterial, there would need to be a significant amount of tests done to ensure that the device has a strong biological performance. Toxicity tests (from the toxicity chart attached with this week's course material), as well as material characteristic tests, such as tensile and compressive stress/strain among others, would be a necessary minimum. If working with cell culture, tests can be done to see how well it promotes growth (if you want cells to grow on it) or if it is effective in killing toxic cells (such as cancerous cells). If the material is meant to be integrated with a device that is used for structural support, like a knee or hip implant, additional tests will need to be done, not only to test its mechanical strength, but also for its longevity. The quality and safety of the material will need to be tested, especially if this is going into a patient. Tests will need to done to determine if there will be any adverse responses in the host or any responses that will negatively affect the function of the biomaterial.
After these basic tests are done on just the biomaterial, there will need to be research trials, in which animals may be used. Pre-clinical and clinical trials should follow.
Ultimately, the more tests that are performed, the better. It can prevent you from having any liability issues.
As stated, this is regulated by ISO 10993 and the toxicity table. This depends on the application and intended use of the new biomaterial and its placement on the body. Whether it is a surface device, external communicating device, or an internal device. Furthermore, it depends on the contact duration. Not all testing is required, this is a guidelines and in many cases a written rationale for not carrying out a certain test may be provided.
As mentioned before, biocompatibility testing must be performed in accordance to ISO 10993 and other FDA relevant standards. The type of testing depends on the type of device: surface, external or implant device. The biocompatibility testing will also depend on the type of contact with the device and the biological effects due to the device contact and the contact duration. For a medical device, there could be a number of different test required depending on the category a device falls.
If a new product is getting ready to be put into the market, there are a lot of testing that needs to be done in order to prove to FDA that it is biocompatible. The ISO10933 table provides a series of tests that can be used to test devices based on which category they fall under. For example, if you developed a patch that will only come in contact with the skin for a limited amount of time, you can avoid most of the biocompatibility testing listed on the table and stick to the cytotoxicity, sensitization and irritation of intracutaneous reactivity tests only. However, if you have a device that will be implanted inside the body for a prolonged time, then you will have to do extra testing including genotoxicity and hemocompatibility.
Biocompatibility testing occurs in the forms of cytotoxicity, irritation, hemocompatibility, sensitization, carcinogenicity, or any other biological effect listed on the ISO-10993-1 toxicity test matrix. For obvious reasons, the quantity of testing done is proportional to the extent and duration to which the medical device interfaces with the patient. Surface devices/treatments that are placed on the skin (such as anti-dryness lotion from Loreal) mainly undergo testing in ADME, cytotoxicity, sensitivity, and irritation since it does not permeate throughout the body. This type of testing used to be done on animal models, but has transitioned to being tested on human skin that has been tissue-engineered from skin-cells in order to attain more accurate results while circumventing the euthanasia of animals. Biocompatibility testing for a more invasive device, such as a cardiac stent involves in vitro and in vivo testing involving systemic toxicity, chronic toxicity testing depending on how long the stent is intended to stay in the patient, as well as implantation, hemocompatibility, carcinogenicity, and genotoxicity. This extensive testing is done to account for any unwanted byproducts released into the blood, which can travel to other parts of the body and result in complications for the patient that were not initially present.
