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Test Method

The biocompatibility of the Vantex CVC with Oligon material (with or without heparin coating) and the chlorhexidine/silver sulfadiazine coated CVC (antiseptic-coated CVC) were evaluated as suggested in the International Standards Organization (ISO) 10993-1-1994 Biological Evaluation of Medical Devices – Part 1: Guidance on Selection of Tests and the FDA General Program Memorandum No. G95-1. The specific test procedures performed were:

In Vivo Tests

  • USP Mouse Systemic Injection – Normal Saline and Vegetable Oil Extracts.

  • USP Rabbit Intracutaneous Irritation – Normal Saline and Vegetable Oil Extracts.

  • Guinea Pig Maximization Test – Normal Saline and Vegetable Oil Extracts.

  • USP Rabbit Intramuscular Implantation with Histological Evaluation – Approximately 7-and 30-Day Implant Duration (considered to be Sub-Chronic Evaluation).

  • Genotoxicity: Mouse Micronucleus Test – Normal Saline and

5% Ethanol in Normal Saline Extracts.

In Vitro Tests

  • Agar Overlay – Solid Sample.

  • Medium Eluate Method (MEM).

  • Blood Compatibility.

  • Genotoxicity: Ames Plate Incorporation Test – Normal Saline

and 5% Ethanol in Normal Saline Extracts.

  • Genotoxicity: Sister Chromatid Exchange Test – Distilled Water and 1% Ethanol in Normal Saline Extracts.

  • Genotoxicity: Mouse Lymphoma Assay – Normal Saline and Ethanol Extracts.

The test articles for this study were treated portions of the representative test samples. This comprised both the internal and external surfaces of the Vantex CVC with Oligon material sample, and only the external treated surface area of the antiseptic-coated CVC. Extracts were prepared at a ratio of 6 cm2 of surface area of each test article per milliliter extraction medium (120 cm2/20 mL) as recommended by both the International Standards Organization (ISO) 10993-12: Sample Preparation and Reference Materials and the United State Pharmacopoeia 23 for material of 0.5 mm thickness.

Exceptions to the test sample size were the heparin coated Oligon Sister Chromatid Exchange Test samples, which was evaluated at 1.0 cm2/mL as part of a whole device evaluation. Blood Compatibility testing of the non-heparin coated Oligon body tubing was performed at 6 cm2/mL but was reduced to 3 cm2/mL due to slight hemolysis noted at the elevated concentration in the static testing of both the material and extract thereof. The reduction in sample to extract concentrations was considered acceptable based on industry standards for materials evaluation for the Blood Compatibility Test and was required due to the known cytotoxic nature of the test article in the Sister Chromatid Exchange Test.

All extracts were prepared at 70 ± 2°C for 24 ± 1 hours as acceptable in the same two guidelines (more elevated temperatures were considered inappropriate given the nature of the base materials and the presence of coatings; whereas, reduced temperatures were not selected as the product was exposed to temperatures similar to the 70°C extraction temperature during the sterilization of the product). The exception to the 70°C extraction which uses a 37 ± 2°C temperature for 24 ± 2 hours per the industry standard test methodology. All studies were conducted in accordance with GLP regulations, in that strict compliance to standard operating procedures was maintained; however, the studies must be considered non-GLP as the protocol, final report, QAU audits and record storage were not in strict compliance to Federal Register 21 CFR Part 58.

Test Results and Discussion

Vantex CVC with Oligon Material Results

The Vantex CVC with Oligon material (non-heparin coated) demonstrated biocompatibility in all test procedures at the maximum concentration evaluated in all procedures except the Blood Compatibility static evaluation of the solid and extract samples. In all other tests, there was no evidence of systemic toxicity, intracutaneous or intramuscular irritation, cytotoxicity, hemolysis (in the dynamic environment more representative of the clinical application), effect on clotting time, or genotoxic potential. The exception to these results was the Blood Compatibility Test on the static samples. Both the solid sample and extracts were all found to be non-hemolytic at levels in excess of the clinical application of the material with the exception of the solid and extract samples in the static environment. When reduced to a sample to extract concentration of 3 cm2/mL, the extract was determined to be non-hemolytic. This solid sample was still determined to be minimally hemolytic (11.6% hemolysis with a non-hemolytic acceptance criteria of < 5% hemolysis) at the reduced concentration. This minimal hemolysis was not considered significant due to the dynamic environment present in the clinical application and the recognized slightly toxic and anti- microbial properties of this Oligon material.

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