The effect of age on functional ACL healing

年龄对 ACL 功能性愈合的影响

• 批准号: 8441832
• 负责人: Martha M Murray
• 金额: $ 71.84万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441832
• 关键词: Adolescent; Affect; Animal Experiments; Animal Model; Animals; Area; Biocompatible Materials; Blood Platelets; Clinical Research; Collagen; Data; Degenerative polyarthritis; Devices; Engineering; Ethylene Oxide; Expenditure; FDA approved; Family suidae; Funding; Gold; Grant; Healed; Human; Implant; Industry; Infectious Agent; Injury; Knee; Ligaments; Modeling; Natural regeneration; Orthopedics; Parents; Patients; Phase; Plague; Preparation; Private Sector; Process; Production; Property; Protocols documentation; Research Personnel; Running; Safety; Site; Solutions; Sterility; Sterilization; Stream; Structure; Techniques; Technology; Tendon structure; Testing; Time; Tissue Engineering; Touch sensation; Toxic effect; Translating; Work; age effect; animal data; anterior cruciate ligament healing; anterior cruciate ligament reconstruction; base; biomaterial compatibility; cost; cytotoxicity; cytotoxicity test; healing; implantation; injured; interest; new technology; novel; parent grant; prevent; repaired; research study; response; scaffold; standard care; standard of care; sterility testing; wound

DESCRIPTION (provided by applicant): We have recently discovered that skeletally immature and adolescent animals have a functionally successful repair response to ACL injury when a tissue engineering repair strategy is used. This strategy utilizes a collagen scaffold with an optimized platelet solution (a collagen-platelet composite, CPC) to enhance healing in the ligament wound site. We discovered that the strength of the ACL after three months of healing using a CPC was equivalent to the strength of an ACL reconstruction graft, the current gold standard of treatment. Further study demonstrated that the post-traumatic osteoarthritis seen in patients and animals alike after ACL reconstruction was not seen in animals undergoing CPC-enhanced repair of the ACL. The aims of this current revision (formerly known as a competing supplement) are to expand the focus of the current parent R01 in order to prepare this new technology for the first-in-human use. The two major requirements this work would fulfill would be 1) to verify and validate a terminal sterilization technique for the collagen scaffold. Our current process involves making the collagen scaffold using a "sterile process" - everything that touches the component materials of the scaffold needs to be sterile, which is expensive and time-consuming. In contrast, terminal sterilization allows for non-sterile processing of the biomaterial and then sterilization of the final product. This results in a 10-fold reduction in manufacturing costs, and the FDA requires a terminal sterilization step, or evidence that one is not possible without harming the device efficacy. The second phase of work would involve biocompatibility studies of the collagen scaffold. This would include testing for cytotoxicity, sensitization, systemic toxicity and implantation testing. The completion of these two phases of study would allow us to use this finalized scaffold in the work to be performed in Aim 2 of the parent R01, thus simultaneously generating the data required by the FDA on the final product and completing the scientific aims of the parent grant with one experiment, rather than having to run a second trial for the FDA clearance. This would save significant expenditures required to translate this technology to human patients. We have already tried to get funding for this requisite supplemental work from industry and private sector investing; however, we have been told this type of novel technology would be too disruptive to current streams of revenue for major orthopedic companies in the area of ACL treatment, and thus, their level of interest in supporting these studies is low. Therefore, this grant mechanism currently represents our sole avenue through to clinical studies and first-in-human use of this novel technique which could result in a paradigm shift in ligament and tendon repair technology. With the time line of the parent grant, this is our only chance to apply for this supplemental funding. PUBLIC HEALTH RELEVANCE: ACL injuries affect over a half million people in the US each year. We have developed a novel technique of treatment ACL injuries using a bio-engineered scaffold to stimulate the ligament to heal and regenerate after injury. This new technique also prevents the post-traumatic osteoarthritis seen after the current gold standard of ACL treatment, ACL reconstruction. This grant would provide funding for the last two critical steps required before going to human trial of this less-invasive technique of ACL repair and regeneration.

描述（由申请人提供）：我们最近发现，当使用组织工程修复策略时，骨骼不成熟和青春期动物对ACL损伤具有功能成功的修复反应。该策略利用具有优化的血小板溶液（胶原蛋白 - 斑块复合材料，CPC）的胶原支架来增强韧带伤口的愈合。我们发现，使用CPC愈合三个月后，ACL的强度等同于ACL重建移植物的强度，ACL重建移植物是当前的金标准治疗标准。进一步的研究表明，在接受ACL的CPC增强修复的动物中，未见ACL重建后患者和动物的创伤后骨关节炎。目前的修订的目的（以前称为竞争补充剂）是扩大当前父级R01的重点，以便为这项新技术做准备，以供第一次人类使用。这项工作将满足的两个主要要求是1）验证和验证胶原蛋白支架的末端灭菌技术。我们当前的过程涉及使用“无菌过程”制作胶原蛋白脚手架 - 触及脚手架的组件材料的所有东西都需要无菌，这是昂贵且耗时的。相比之下，末端灭菌允许对最终产物的生物材料进行非紧密处理。这导致制造成本降低了10倍，而FDA需要一个末端灭菌步骤，或者证明不损害设备功效的情况不可能。工作的第二阶段将涉及胶原支架的生物相容性研究。这将包括测试细胞毒性，敏化，全身毒性和植入测试。这两个研究阶段的完成将使我们能够在工作中的AIM 2中使用此最终确定的脚手架，从而同时生成FDA对最终产品所需的数据，并通过一项实验完成父母赠款的科学目标，而不是必须对FDA清除进行第二次试验。这样可以节省将该技术转化为人类患者所需的巨大支出。我们已经试图从行业和私营部门投资的这项必要的补充工作中获得资金；但是，我们被告知，这种新型技术将对ACL治疗领域的主要骨科公司目前的收入流太破坏，因此，他们对支持这些研究的兴趣水平很低。因此，这种赠款机制目前代表了我们唯一的途径，用于临床研究和人类的首次使用这种新技术，这可能会导致韧带和肌腱修复技术的范式转移。借助父母赠款的时间表，这是我们申请此补充资金的唯一机会。 公共卫生相关性：ACL受伤每年影响超过50万人。我们已经使用生物工程脚手架开发了一种新型的治疗ACL损伤技术，以刺激韧带损伤后愈合和再生。这项新技术还防止了ACL治疗当前金标准ACL重建后看到的创伤后骨关节炎。该赠款将为对ACL修复和再生技术不那么侵入的技术进行人体试验之前的最后两个关键步骤提供资金。