Terminal Sterilization of Tendon Allografts Using Supercritical CO2- Phase II

使用超临界 CO2 对肌腱同种异体移植物进行最终灭菌 - 第二阶段

• 批准号: 7324718
• 负责人: Renee Christopher
• 金额: $ 44.06万
• 依托单位: NOVASTERILIS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7324718
• 关键词: Address; Adopted; Affect; Allografting; American; Analysis of Variance; Articular ligaments; Biomechanics; Carbon Dioxide; Clinical; Collaborations; Colony-forming units; Condition; Control Groups; Data; Development; Disease; Ethylene Oxide; Exposure to; Funding; Hour; Impairment; Implant; Industry; Injury; Medical Device; Methods; Monitor; Musculoskeletal; Names; Neuro-Oncological Ventral Antigen 2; One-Step dentin bonding system; Operative Surgical Procedures; Orthopedics; Parvovirus; Patients; Phase; Physicians; Physiological; Procedures; Process; Property; Reporting; Rotator Cuff; Safety; Shoulder; Societies; Standards of Weights and Measures; Sterility; Sterilization for infection control; Surgeon; System; Technology; Tendon Injuries; Tendon structure; Testing; Time; Tissue Banks; Tissues; Transplantation; United States; United States Food and Drug Administration; Viral; Virus; Virus Inactivation; achilles tendon; bone; commercialization; cost; design; dosage; irradiation; microorganism; musculoskeletal injury; pathogen; repaired; size; soft tissue; tyvek

DESCRIPTION (provided by applicant): Currently, most tissue banks use a two step process to sterilize soft tissue allografts. The initial step reduces the bioburden with the second step in sterilization resulting in "terminal sterilization". The direct result of Phase 1 funding has been the development of a terminal sterilization technology using supercritical CO2 and a proprietary additive that will allow tissue banks to easily process soft tissue allografts to a sterility assurance level equal to that called for in medical devices (SAL6) in a one step process. Sterilization was confirmed according to the standards in AMI/ISO 11737-1 and 2. The sterilization technology is capable of inactivating a wide variety of microorganisms at concentrations of greater than 106 colony forming units (CFUs) in a half cycle. Utilizing sterilization times as determined from D-value calculations according to the methods of Stumbo-Murphy-Cochran (terminal sterilization at 2.5 hours and overkill at 4 hours) we assessed the affect of our supercritical CO2 process on the biomechanical properties of bone-tendon-bone (BTB) patellar tendon allografts. Biomechanical data obtained revealed no significant difference between the supercritical CO2 sterilized and control group (ANOVA statistical analysis and paired T-testing). The technology developed in Phase 1 will offer an alternative to methods of sterilization of soft tissue allografts used by tissue banks. Musculoskeletal conditions (diseases and disorders) have a tremendous impact on society. In the United States alone, musculoskeletal conditions cost society an estimated $254 billion yearly with 1 out of every 7 Americans reporting a musculoskeletal impairment. Each year, 28.6 million Americans incur a musculoskeletal injury with approximately 7.5 million musculoskeletal procedures performed by physicians. The importance of allograft tissue in the treatment of orthopedic patients has grown rapidly during the last decade. Tendon, ligament and joint injuries represent 45% of the musculoskeletal injuries each year. Tendon injuries are especially common, requiring surgical repair to replace shoulder rotator cuff tendons (51,000/year), achilles tendon (44,000/year), and the patellar tendon (42,000/year) to name a few. Concomitant with the increased demand for tissue has been the increase potential of exposures to pathogens. There is high potential for bacterial or viral contamination of allograft tissue without adequate secondary sterilization processing. Thus, the safety of allograft tissue has become a primary focus for the tissue bank industry, clinicians, and the FDA. Phase II funding will allow us to further optimize the sterilization process by addressing packaging (double packaging and header packs) as recommended by tissue banks and orthopedic surgeons. This packaging will result in a terminally sterilized product ready for direct transfer for transplant. The importance of allograft material in the treatment of orthopedic patients has grown rapidly during the last decade, which leads to a growing concern for an increased potential of exposure to pathogens. Viral and bacterial contamination of allograft tissue without adequate secondary sterilization processing remains an issue. Thus, the safety of allograft tissue has become a primary focus for the tissue bank industry, clinicians and the FDA. The tissue bank industry and processing centers have invested numerous hours and a large amount of money into methods of processing to achieve a high quality and safe. By providing a one step terminal sterilization process (sterilized grafts in final packaging), our company would be adding value and safety to the processing that occurs in the tissue bank industry. The only two processes capable of terminal sterilization of allografts are ethylene oxide and gamma irradiation which suffer from major drawbacks if used at a concentration to achieve SAL6 thus requiring a two step process to minimize the dosage. Terminal sterilization using our supercritical CO2 process has the potential to add a one step validated terminal sterilization process to tissue banking while decreasing the costs of processing and generating a safer product. Funding for Phase I has allowed us to show the feasibility of supercritical CO2 as a method of overcoming the current limited sterilization options. Funding of phase II will allow us to take the next steps towards successful commercialization by further optimization of packaging design (allowing for a terminally sterilized product of various sizes) and other pathogenic inactivation in soft tissue allografts.

描述（由申请人提供）：目前，大多数组织库使用两步过程对软组织同种异体移植物进行灭菌。初始步骤降低了生物负载，第二步灭菌导致“最终灭菌”。第1阶段资助的直接结果是开发了一种使用超临界CO2和专有添加剂的终端灭菌技术，该技术将使组织库能够轻松地将软组织同种异体移植物处理到与医疗器械（SAL 6）中要求的无菌保证水平相同的一步过程中。根据AMI/ISO 11737-1和2中的标准确认灭菌。该灭菌技术能够在半周期内灭活浓度大于106个菌落形成单位（CFU）的各种微生物。根据Stumbo-Murphy-Cochran的方法（2.5小时的最终灭菌和4小时的过度杀灭），利用D值计算确定的灭菌时间，我们评估了超临界CO2工艺对骨-肌腱-骨（BTB）髌腱同种异体移植物生物力学性能的影响。获得的生物力学数据显示超临界CO2灭菌组和对照组之间无显著差异（ANOVA统计分析和配对T检验）。第一阶段开发的技术将为组织库使用的软组织同种异体移植物的灭菌方法提供一种替代方法。肌肉骨骼疾病（疾病和失调）对社会有着巨大的影响。仅在美国，肌肉骨骼疾病每年给社会造成的损失估计为2540亿美元，每7个美国人中就有1个报告肌肉骨骼损伤。每年有2860万美国人遭受肌肉骨骼损伤，医生进行了大约750万次肌肉骨骼手术。同种异体移植组织在骨科患者治疗中的重要性在过去十年中迅速增长。肌腱、韧带和关节损伤占每年肌肉骨骼损伤的45%。肌腱损伤尤其常见，需要手术修复以替换肩袖肌腱（51，000/年）、跟腱（44，000/年）和髌腱（42，000/年）。随着对组织需求的增加，接触病原体的可能性也在增加。如果不进行充分的二次灭菌处理，同种异体移植物组织极有可能受到细菌或病毒污染。因此，同种异体移植组织的安全性已成为组织库行业、临床医生和FDA的主要关注点。第二阶段的资金将使我们能够通过解决组织库和整形外科医生推荐的包装（双层包装和顶盖包装）来进一步优化灭菌过程。该包装将导致最终灭菌的产品准备好直接转移用于移植。 在过去的十年中，同种异体移植材料在骨科患者治疗中的重要性迅速增长，这导致人们越来越关注暴露于病原体的可能性增加。没有充分的二次灭菌处理的同种异体移植组织的病毒和细菌污染仍然是一个问题。因此，同种异体移植组织的安全性已成为组织库行业、临床医生和FDA的主要关注点。组织库行业和处理中心已经投入了大量的时间和大量的资金到处理方法中，以实现高质量和安全。通过提供一步终端灭菌过程（最终包装中的灭菌移植物），我们公司将为组织库行业中发生的处理增加价值和安全性。能够对同种异体移植物进行最终灭菌的仅有两种方法是环氧乙烷和γ辐照，如果以达到SAL 6的浓度使用，则存在主要缺点，因此需要两步方法来最小化剂量。使用我们的超临界CO2工艺进行的最终灭菌有可能为组织库添加一步经验证的最终灭菌工艺，同时降低加工成本并生产更安全的产品。第一阶段的资金使我们能够证明超临界CO2作为克服当前有限灭菌选择的方法的可行性。第二阶段的资金将使我们能够通过进一步优化包装设计（允许各种尺寸的最终灭菌产品）和软组织同种异体移植物中的其他病原体灭活，朝着成功商业化迈出下一步。