Biocompatibility irritation testing

A number of important characteristics must be taken into consideration in addition to the efficacy of the products antimicrobial treatment. Biocompatibility is one of those characteristics. According to the International Organization for Standardization (ISO) 10993-1, Biological Testing of Medical and Dental Materials and Devices, all device materials must undergo cytotoxicity, sensitization and irritation testing as a minimum. 

Although the initially reported tissue compatibility tests for subcutaneous implants of poly(BPA-iminocarbonate) were encouraging (41,42), it is doubtful whether this polymer will pass more stringent biocompatibility tests. In correspondence with the properties of most synthetic phenols, BPA is a known irritant and most recent results indicate that BPA is cytotoxic toward chick embryo fibroblasts in vitro (43). Thus, initial results indicate that poly(BPA-iminocarbonate) is a polymer with highly promising material properties, whose ultimate applicability as a biomaterial is questionable due to the possible toxicity of its monomeric building blocks. 

After 7 days, the acute inflammatory response at the implantation site was evaluated. Bisphenol A resulted in a moderate level of irritation at the implantation site and was clearly the least biocompatible test substance. Tyrosine derivatives containing the benzyloxycar-bonyl group caused a slight inflammatory response, while all other tyrosine derivatives produced no abnormal tissue response at all. These observations indicate that tyrosine dipeptide derivatives, even if fully protected, are more biocompatible than BPA, a synthetic diphenol. ... 

As to the biomaterial for human tissue replacement, it is necessary to demonstrate if the material has any effect on the biological properties of the tissue. Bioceramics exhibit some possible toxic reactions due to metal ions leaching from the ceramics, resulting in the tissue dying or heavy reactions. In this experiment, cytotoxicity test, hemolysis test as well as skin irritation were conducted to value the biocompatibility of the porous AI2O3 ceramics. 

The modified polymer beads [347] passed all of the standard battery of biocompatibility tests required by the International Organization for Standardization guidelines (ISO 10993). The tests included in vitro coagulation tests (plasma recalcification time), hemolysis study (extraction method), cytotoxicity study using the ISO elution method, etc. In in vivo experiments, extracts of the polymer beads did not elicit pyrogenic irritation or sensitization reactions in laboratory animals (acute systematic toxicity study in the mouse, acute intracutaneous reactivity study in the rabbit, rabbit pyrogen study). 

The extract dilution type of cell culture assay requires a solvent extraction of the biomaterial under consideration and testing of this extract, most commonly at various dilutions, for evidence of cytotoxicity and cellular interaction. This type of cell culture assay finds its most common use in providing information for regulatory compliance. As identified in the preceding Materials for Medical Devices section and in Table 1, low-molecular-weight extractables are of concern regarding biocompatibility. The extraction assay, carried out with a series of solvents that are hydrophilic and hydrophobic, permits examination of the potential cytotoxicity of extracts and the identification of materials within a biomaterial that may be cytotoxic. These types of assays ultimately permit identification and characterization of cytotoxic materials within biomaterials or the lack of cytotoxicity, as well as providing correlation with in vivo assays such as sensitization, irritation, intracutaneous (intradermal) reactivity, and other tests where the in vivo injection of extracts is required. 

The biocompatibility tests brought forth die lack of a sensitizing, irritating and cytotoxic potential of the tested dressing (bandage). ... 

The safety and biocompatibility of the dmg delivery system and its components have been extensively tested according to Tripartite Biocompatibility Testing Guidelines (Center for Devices and Radiological Health, 1993). Specifically, these studies have shown that PLA is nontoxic and the hazard potential of NMP is insignificant. Additional preclinical tests to evaluate tissue irritation potential, implantation effects, and biodegradation have been completed for formulations prepared with PLA, PLG, and PLC polymers dissolved in NMP or DMSO. The pharmacokinetics of these formulations have also been tested for specific dmg delivery applications. 

Biocompatibility, especially safety and mildness to skin, are very important properties of interest for the application of AAS. Animal tests such as the Draise method for primary eye and skin irritation and the maximization test for sensitization have been widely used in the past. Recently, an alternative or in vitro test was actively developed for the purpose of refining, reducing, and replacing the animal test. Although there are still no perfect alternatives... 

At the end of the study, the implanted sites are retrieved and processed histopatho-logically. A pathologist evaluates the sites and scores them for a local tissue reaction. The scores from the control sites, which will be implanted with a proven biocompatible material, are subtracted from the scores of the test sites. The final score then categorizes the test material into a gradation of irritancy. 

Table II. Biocompatibility Test Methods ISO 10993-5 Cytotoxicity ISO 10993-10 Sensitization ISO 10993-10 Irritation Others...

The three areas of biocompatibility testing, cytotoxicity, sensitization, and irritation mentioned above are by no means all the tests that may be needed when determining the toxicity of a treated medical device. These three test areas are mandated by ISO 10993-1, Guidance on the Selection of Tests and its FDA counterpart, blue book memorandum G95-1, however, other tests listed in this standard may need consideration and are dependent mainly on the device and where it will be used in the human body. 

P4HB and P3HB-4HB have been evaluated in preclinical tests reconunended by the FDA for medical devices. These tests include cytotoxicity, sensitization, irritation and intracutaneous reactivity, hemocompatibility, and implantation. Thus for example, P4HB films and sutures were subjected to a complete series of biocompatibility test protocols that were performed in accordance with the FDA s GLP regulations as set forth in 21 CFR, part 58, as well as ISO 10993-1. The test results confirmed that P4HB is nontoxic and biocompatible (Martin DP, personal communication). 

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