Injectable biomaterials requirements

FDA testing and previous studies have verified that 150-250 cP is an ideal range for decreased sodium alginate injection resistance in many standard over-the-wire microcatheter systems and increased calcium alginate stability in gel form (Becker et al, 2005 2007). As for newer flow-directed microcatheter systems, an injectable biomaterial requires a lower alginate viscosity range (1-150 cP) to accommodate the microcather s minimal inner diameter. 

The two most important areas of research when developing an injectable biomaterial for potential human use are (1) material characterization and (2) biocompatibility testing. Material characterization requires extensive rheological testing to assess a material s delivery performance and mechanical stability. The following lists summarize the general material characterization tests required by the FDA. 

The majority of biocompatibiUty testing must be performed to Good Laboratory Practice (GLP) standards, especially those tests with standardized procedural and evaluation criteria. Therefore, it is often beneficial to contract these studies to an outside laboratory that specializes in biocompatibihty testing (e.g. Toxikon, Bedford, MA NAMSA, Northwood, OH). Several GLP tests are required by the FDA to assess an injectable biomaterial s purity, toxicity profile, irritation and sensitization profile, tissue and blood reactivity, and mutagenic profile. These tests are required on the final device as well as any components of the device that may come in contact with human tissues or fluids. Table 14.1 summarizes the in vitro testing requirements expected for a new injectable biomaterial, as disclosed in the FDA s IDE preparation documents (FDA, 2009). 

Table 14.2 summarizes the in vivo testing requirements expected for a new injectable biomaterial, as disclosed in the FDA s IDE preparation documents (FDA, 2009). 

Note Muscle implantation is the initial survival implant study required by the FDA. Testing in a more representative model for the device, as well as long-term survival studies in an in vivo model appropriate for the injectable biomaterial (survivals ranging from 3 months to 1 year), are also required. 

If the device also includes a drug component, then additional testing beyond the IDE may be required by the Center For Drug Evaluation and Research (CDER). However, if the drug is already approved, then the additional testing focuses on the interaction and compatibility of the drug with the injectable biomaterial. 

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. 

An impurity level as low as 5ppb may also be inadequate when the biomaterial is used as a rapidly dispersible injectable implant. Five parts per billion is the detection limit of the highly sensitive immunoblot technique. Fortunately, adequate purification of protein-based polymers used at 30 mg quantities has been achieved at BRL, and adequate purification has been demonstrated for the most stringent of conditions, where an injectable implant totally disperses having unloaded all of its impurities in a few days time. To have passed such a stringent test provides the desired gold standard for purification. Now it will be useful to increase the sensitivity of impurity detection by means of radiolabeling and to establish quality control for the level of purity required when... 

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