Biocompatibility tests

Biocompatibility is an essential criterion for the use of plastics in medical technology [292]. That is usually why many biocompatibility tests are performed on 

Most parts of ISO 10993 [293] used today were published in the early 1990s and revised over the course of the last years. Additional parts are still circulating in draft form. The nomenclature defined in this standard has also been assumed by the FDA. In July 1995, the FDA published a document generally called the Blue Book Memorandum . In it, ISO 10993 [293] is fundamentally recognized by the FDA, while also requiring additional tests for a number of products. Table 2.23 compiles a list of ISO and FDA guidelines for biocompatibility tests [292]. 

Plastics to be used in the medical industry are typically marketed under the term medical grade . This term has no legal significance and does not indicate fulfillment of standard requirements of any kind [292]. 

The by far most established document available with regard to medical grade plastics is the USP Class VI Certificate. USP (U. S. Pharmacopeia) class tests involve a series of tests to demonstrate that the plastic material is suitable for pharmaceutical containers. These tests are also expedient for materials used for syringes, blood bags, and similar products [292]. 

A comparison of the USP tests with ISO 10993 requirements shows little similarity. USP class VI tests do not consider the requirements for cytotoxicity, sensitization (both required for all medicinal applications), and hemocompatibility. USP tests do not consider the long-term effects of materials on the body (genotoxicity, subchronic and chronic toxicity, and long-term implants). USP class VI certificates contribute little to the reduction of tests required for a final product [292]. 

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Hybrid organosilicon-organophosphazene polymers have also been synthesized (15-18) (structure ) (the organosilicon groups were introduced via the chemistry shown in Scheme 11). These are elastomers with surface contact angles in the region of 106°. Although no biocompatibility tests have been conducted on these polymers, the molecular structure and material properties would be expected to be similar to or an improvement over those of polysiloxane (silicone) polymers. 

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. ... 

In order to test the tissue compatibility of tyrosine-derived poly-(iminocarbonates), solvent cast films of poIy(CTTH) were subcutaneously implanted into the back of outbread mice. In this study, conventional poly(L-tyrosine) served as a control (42). With only small variations, the experimental protocol described for the biocompatibility testing of poly(N-palmitoylhydroxyproline ester) (Sec. III. 

Kasten, F. H., Pineda, L. F., Schneider, P. E., Rawls, H. R. Foster, T. A. (1989). Biocompatibility testing of an experimental fluoride releasing resin using human gingival epithelial cells in vitro. In Vitro Cellular Development Biology, 25, 57-62. 

Nakamura, M., Kawahara, H., Imia, K., Tomoda, S., Kawata, Y. Hikari, S. (1983). Long-term biocompatibility test of composite resins and glass-ionomer cement (in vitro). Dental Materials Journal, 1, 100-12. 

Silk fibers or monolayers of silk proteins have a number of potential biomedical applications. Biocompatibility tests have been carried out with scaffolds of fibers or solubilized silk proteins from the silkworm Bombyx mori (for review see Ref. [38]). Some biocompatibility problems have been reported, but this was probably due to contamination with residual sericin. More recent studies with well-defined silkworm silk fibers and films suggest that the core fibroin fibers show in vivo and in vivo biocompatibility that is comparable to other biomaterials, such as polyactic acid and collagen. Altmann et al. [39] showed that a silk-fiber matrix obtained from properly processed natural silkworm fibers is a suitable material for the attachment, expansion and differentiation of adult human progenitor bone marrow stromal cells. Also, the direct inflammatory potential of silkworm silk was studied using an in vitro system [40]. The authors claimed that their silk fibers were mostly immunologically inert in short and long term culture with murine macrophage cells. 

The synthetic polymeric components as well as their combinations with proteins such as human serum albumin (HSA), bovine serum albumin (BSA), human serum albumin/a-interferon mixtures (HSA-IFNa) and myoglobin (MYO) did not give any negative response to in vitro and in vivo biocompatibility tests, such as platelet aggregation, complement activation, acute toxicity, and acute thromboembolic potential. 

Biocompatibility test scheme adjusted for FCLs for ophthalmic use... 

This chapter presents the state of the art of the use of highly fluorinated liquids in ophthalmology and perspectives of future applications in the eye. In different medical disciplines, the characteristics of these fluids are directly used, like in the case of ocular endotamponades in ophthalmology, of gas carriers in liquid ventilation, or of preservation and transport media in transplantation medicine [1-3]. For these applications, the highly fluorinated liquids are used in a purified form or as mixtures. The intended effect is created by the physicochemical characteristics themselves. The extraordinary behaviour of the fluorocarbon liquids (FCLs) requires specialised biocompatibility testing, adjusted to this class of components. 

This experience is an indication that biocompatibility testing has to be adjusted for each device, and established animal models must be questioned if new classes of substances are to be tested. Standardised toxicological tests may be suitable for substances known at that time when these tests were developed. There is a need for the introduction of new types of cell culture tests as well as for better animal models and more suitable in vivo tests [49]. 

Mendes, S. C.,Bovell, Y. R.,Reis,R. L., Cunha, A. M., deBruijn, J. D., vanBlitterswijk, C. A. (2001). Biocompatibility testing of novel starch-based materials with potential application in orthopaedic surgery. Biomaterials., 22,2057-2064. 

Adhesives used in medical devices are tested for their effect on cells (cytotoxicity), blood constituents (hemolysis), and adjacent tissues, and for overall systemic effect. Several classes of biocompatibility testing exist. Adhesive suppliers, however, generally test to the following guidelines that have been established for toxicological properties and biocompatibility ... 

Such biocompatibility tests are only a guideline, and more extensive and specific testing may be required for certain device manufacturers. The extent and nature of the testing can also vary from adhesive supplier to adhesive supplier. 

Biocompatibility tests vary for short-term versus long-term contact with tissue. Depending on whether the contact is with skin or internally, many standard tests have been developed for biocompatibility screening. Although many tests are predictive of the responses observed during use of devices in humans, biocompatibility of a device is ultimately only verified after extensive human clinical trials and general use in the population. 

Noncontact devices These are devices that do not contact the patient s body directly or indirectly in vitro diagnostic devices). Regulatory agencies rarely require biocompatibility testing for these devices. X ISO evaluation tests for consideration. 

The Canine Model. While ex vivo models often are considered to be an improvement over in vitro biocompatibility test systems, the problem of describing extremely complex blood—polymer interactions still remains. In this study, we used radioisotope-labeled proteins and platelets and scanning electron microscopy. In other studies, we applied immunolabeling techniques and transmission electron microscopy. The application of these tools to an in vivo or ex vivo system provides more pertinent data than that often obtained in an in vitro system. Through this approach we hope to gain some insights into the complicated interactions of blood with biomaterials. 

Michel R (1987) Trace metals in biocompatibility testing. CRC Critical Reviews in Biocompatibility 3 235-317. 

R. E. Wilsnack, "Quantitative cell culture biocompatibility testing of medical devices and correlation to animal tests". Biomater. Med. Devices Artif. Organs 4(3 4) 235-261, 1976. 

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). 

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