Biocompatibility tests

Biocompatibility testing is a process of evaluating of compatibility of a material or medical device with a biological system to ensure that it is not toxic or harmful and not causing adverse effects. The toxicological endpoints to be considered to measure the safety of a medical device are described below. This listing does not imply that all these endpoints are necessary for any given device nor does it indicate that these are the only available tests.

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1.    Cytotoxicity Test
2.    Skin Sensitization Test
3.    Irritation Test
4.    Acute Systemic Toxicity
5.    Material Mediated Pyrogen Test
6.    Subacute Toxicity
7.    Subchronic Toxicity
8.    Chronic Toxicity
9.    Genotoxicity
10.    Implantation Tests
11.    Hemocompatibility Tests
12.    Carcinogenicity study
13.    Reproductive And Developmental Toxicity
14.    Degradation test

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The number of tests to be considered for a medical device depends on the nature of body contact and duration of body contact. Depending on the materials used in the medical device, its clinical intended use and the risk associated with the device, additional tests may also need to be considered. 

Cytotoxicity Test:
Cytotoxicity tests are performed in mammalian cell lines. These in vitro tests are useful in assessing the toxicity or irritancy potential of the medical devices or medical device extracts. The cytotoxicity test is a preliminary but robust test. It provides an excellent way to screen materials before in vivo tests.

Types of Cytotoxicity tests

 

 

 

 

 

 

 

 

 

 

 

 

Skin sensitization test:
Sensitization studies help to determine whether a medical device or its extract has the potential to elicit allergic or hypersensitivity reactions. The test evaluates both local and systemic effects after repeated or prolonged exposure. These allergic or hypersensitivity reactions involve immunologic mechanisms.
 

Types of Skin sensitization tests

• Guinea pig maximization test (GPMT) 

• Closed-patch test (Buehler test)

• Murine local lymph node assay (LLNA)

 

Irritation tests:
The irritation tests are used to evaluate the local irritation potential of devices, materials or extracts of devices at the site of contact. Both in vitro and different in vivo test methods are available for evaluating the irritation potential. The type of test methods to be selected is based on the route of exposure (skin, eye, oral, mucosal) of the medical device in patients.

Types of Irritation tests

In vitro irritation test 
     In vitro reconstructed human epidermis model
 

In vivo Tests
     Dermal Irritation test
     Intracutaneous Irritation test
     Ocular irritation test
     Oral mucosa irritation test
     Penile irritation test
     Rectal irritation test
     Vaginal irritation test
 

Acute systemic toxicity test
This test is used to determine the systemic (as opposed to local) toxic effects after a single administration of medical device extracts. The polar and non-polar extracts of the medical devices are used in this study. The polar and non-polar extracts are administered through intravenous and intraperitoneal routes to the mice at a high dose volume and observed for toxic signs just after injection and at four other time points.
 

Material Mediated Pyrogen Test:
The Material Mediated Pyrogen test evaluates the potential of a medical device extract to cause a pyrogenic response or fever when introduced into the rabbit blood. A number of chemicals have the potential to induce fever. The LAL test doesn’t detect the chemicals causing pyrogenicity. Hence Rabbit pyrogen test has been included in the battery of Biocompatibility tests to detect the pyogenic effect of the medical device extract. 
 

Subacute toxicity study:
Subacute toxicity is used to assess the potential harmful systemic arising from short-term repeated exposure to medical device or medical device extracts. The treatment duration is between 24 hours to 28 days in rodents. This study can be conducted either by the implantation or extraction methods. In a subacute toxicity study by intravenous administration of test item extract, the treatment duration is >24 h but <14 d. 

 

Subchronic toxicity study:
Subchronic toxicity is used to assess the adverse systemic arising from repeated exposure to a medical device or medical device extracts for a part of the life span. The treatment duration is 90 days in rodents but does not exceed 10 % of the lifespan of other species. This study can be conducted either by the implantation or extraction methods. In the subchronic toxicity study by intravenous administration of test item extract, the treatment duration is 14 to 28 days for rodents and non-rodents, respectively.
 

Chronic toxicity study:
Chronic toxicity is used to assess the adverse systemic arising from repeated or continuous administration of the test item for a significant part of the life span. The treatment duration is six months to 12 months. Generally, this study is conducted by the implantation method. 
 

Genotoxicity studies:
Genotoxicity evaluations are used to detect mutagens, substances that can directly or indirectly induce genetic damage through various mechanisms. It’s a battery of in vitro and in vivo tests. The in vitro genotoxicity test battery includes a gene mutation test in bacteria and one test in mammalian cell lines. If the results of two in vitro tests are negative, then further animal genotoxicity tests are not necessary. 

 

Implantation Tests:
Implant studies are used to assess the local effects at the implantation site. This test is performed on medical devices or biomaterials that directly contact living tissue other than skin. These tests can evaluate devices that, in clinical use, are intended to be implanted for either short-term or long-term periods. To provide a reasonable assessment of safety, the implant study should closely approximate the intended clinical use. The interaction of both absorbable and non-absorbable medical devices with the local tissues can be assessed, primarily through the histopathological analysis of implant sites. 

 

Hemocompatibility:
The medical devices that come in contact with blood either directly or indirectly shall be tested for hemocompatibility to establish their safety. In hemocompatibility tests, check whether the medical device can either disrupt the blood cells (hemolysis) or activate the coagulation pathways (thrombogenicity) and/or the complement system. The appropriate tests for the circulating blood-contacting devices depend on nature and degree of contact. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Carcinogenicity study:
The carcinogenicity study is performed to assess the tumorigenic potential of the medical device. In this study, the test item is exposed to the major life span of the animals. Hence the test duration in rats is 24 months and in mice is 18 months. Carcinogenicity testing of devices is expensive and time-consuming. There are ways to address and wave off carcinogenicity studies. However for all the devices which has long term contact with the patient, the carcinogenicity end point shall be sufficiently addressed.

 

Reproductive and Developmental Toxicity:
These studies evaluate the potential effects of medical devices or medical device extracts on fertility, reproductive function, prenatal and early postnatal development. This shall be addressed for specific devices. 

 

Degradation test:
The degradation test is required for all absorbable medical devices. In the case of absorbable medical devices, leachable substances may get incorporated into the medical devices during the manufacturing process or the substances may be generated and released as a consequence of its degradation. Hence degradation test shall be conducted to assess the unacceptable adverse systemic and/or local effects of these substances on surrounding cells or tissues.