The Effect of Age on Functional ACL Healing

年龄对 ACL 功能愈合的影响

• 批准号: 7887686
• 负责人: Martha M Murray
• 金额: $ 69.03万
• 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/7887686
• 关键词: Acute; Adolescent; Adult; Affect; Animals; Anterior Cruciate Ligament; Back; Biomechanics; Blood Platelets; Blood Vessels; Caring; Cartilage; Cartilage injury; Cell Density; Cells; Collagen; Contralateral; Degenerative polyarthritis; Erythrocytes; Failure; Family suidae; Fibroblasts; Funding; Grant; Growth Factor; Healed; Histology; Impaired wound healing; Implant; India ink stain; Injury; Joints; Knee; Leg; Ligaments; Limb structure; Meniscus structure of joint; Miniature Swine; Modeling; Operative Surgical Procedures; Outcome Measure; Patients; Population; Procedures; Process; Property; Relative (related person); Risk; Rupture; Site; Surgical sutures; Tissue Engineering; Tissues; Work; Wound Healing; age effect; anterior cruciate ligament healing; anterior cruciate ligament reconstruction; anterior cruciate ligament rupture; articular cartilage; cell motility; clinically relevant; cost; density; design; functional restoration; healing; immature animal; improved; in vivo; injured; injury and repair; juvenile animal; ligament injury; mature animal; migration; novel; premature; primary outcome; public health relevance; repaired; response; scaffold; secondary outcome; standard care; statistics; success; wound

DESCRIPTION (provided by applicant): An exciting finding in the first funding cycle of this grant is that skeletally immature animals have a functionally successful repair response to ACL injury, whereas adolescent and adult animals do not. We postulate that the impaired ACL healing noted in adolescents and adults could be improved if the fundamental biologic processes of increased cellular migration and proliferation found with immature ACL cells and repair tissue could be recapitulated in the adolescent animals using our novel "enhanced ACL repair" strategy. In this competitive renewal, we will determine if the impaired healing potential of adolescent ACL tears can be improved in vivo by using an enhanced repair strategy in which a scaffold stimulates increased cellular density of the repair tissue by facilitating fibroblast migration and proliferation within the wound site. We propose to study the effects of these additives in both the ideal acute repair situation, and in the more clinically relevant case in which the repair is delayed by 2, 4 or 6 weeks in the following two Specific Aims: Aim 1: Evaluate the effect of increasing the cellular density of the ACL repair tissue on functional healing after an immediate repair of a ruptured adolescent ACL. Hypothesis 1a: Tissue engineered scaffolds that increase the cellular density of the ACL repair tissue will have a higher yield load and linear stiffness and lower AP knee laxity after 15 weeks of healing than repairs using scaffolds which impede cellular population of the wound site. Hypothesis 1b: An increase in cell density is related to an increase in yield load and stiffness and a decrease in AP knee laxity. Hypothesis 1C: The repairs augmented with a tissue engineered scaffold containing platelets or erythrocytes will have a higher yield load and linear stiffness and lower AP knee laxity than repairs with collagen alone or ACL reconstruction. Aim 2: Establish the effect delaying repair on the functional healing of the ACL. Hypothesis 2a: The delay of primary repair by 2, 4 or 6 weeks will result in changes in the yield load and linear stiffness of an enhanced ACL repair relative to the acute condition. Hypothesis 2b: A greater degree of cartilage and meniscal damage will be present in knees undergoing repair at 6 weeks as compared to the immediate repair situation. For both Aims our well-characterized adolescent mini pig model of ACL injury and repair will be utilized. The primary outcome measures will include biomechanics (AP knee laxity, ligament structural properties) and histology (cellular density and vascular density). Secondary outcome measures include cartilage injury (India ink staining and histology of the menisci and articular cartilage) and the material properties of the repair. The studies in the proposal are designed to determine whether the impaired ACL healing noted in adolescents and adults could be improved if the repair tissue in these populations could be made to more closely resemble the repair tissue in immature animals using our novel "enhanced ACL repair" strategy. Success in this endeavor could improve the care of hundreds of thousands of adolescent and adult patients with ACL tears each year. PUBLIC HEALTH RELEVANCE: An estimated 300,000 to 500,000 patient each year in the US sustain a tear of the anterior cruciate ligament (ACL). Even with current surgical treatments for this injury, the risk of premature osteoarthritis in these patients approaches 80% at only 14 years out from the injury. For the hundreds of thousands of adolescents this injury affects, that is a troubling statistic. Our work focuses on improving the repairs of these injuries. In our previous grant period, we discovered that young animals heal ligament injuries better than adolescent or adult animals. In this next study, we propose to find out if the impaired ACL healing noted in adolescents and adults could be improved if the repair tissue in these populations could be made to more closely resemble the repair tissue in immature animals if the repairs are supplemented with a scaffold designed to deliver the right growth factors to the ACL tear. Success in this endeavor could improve the care of hundreds of thousands of adolescent and adult patients with ACL tears each year.

描述（由申请人提供）：这笔赠款的第一个融资周期中的一个令人兴奋的发现是，骨骼不成熟的动物对ACL损伤具有功能成功的修复反应，而青春期和成年动物则没有。我们假设，如果使用我们的新颖的“增强的ACL修复”策略，可以在青少年动物中概括细胞迁移和增殖的基本生物学过程，并在青少年动物中发现了增加细胞迁移和增殖的基本生物学过程，那么在青少年和成年人中指出的ACL愈合受损，可以改善受损的ACL愈合受损的ACL愈合受损的ACL愈合。在这种竞争性更新中，我们将通过使用增强的修复策略来确定在体内是否可以改善青少年ACL撕裂的愈合潜力，在这种策略中，脚手架通过促进伤口部位的成纤维细胞迁移和增殖部位促进修复组织的细胞密度增加。我们建议在理想的急性修复情况下研究这些添加剂的效果，以及在以下两个具体目的中，修复延迟2、4或6周的更临床相关的情况下：AIM 1：评估ACL修复组织的细胞密度在立即修复后，会增加ACL修复组织的细胞密度。假设1a：组织工程的支架，增加了ACL修复组织的细胞密度，恢复15周后，与使用阻碍伤口部位的细胞群体的脚手架相比，修复15周后，屈服载荷和线性刚度和膝关节松弛较低。假设1b：细胞密度的增加与屈服负荷和刚度的增加以及AP膝关节松弛的降低有关。假设1C：与单独使用胶原蛋白或ACL重建的维修相比，用组织工程脚手架进行的维修将具有更高的屈服载荷和线性刚度和较低的AP膝关节松弛。目标2：确定延迟修复对ACL功能愈合的效果。假设2a：初级维修的延迟延迟2、4或6周将导致相对于急性条件增强的ACL修复的屈服负荷和线性刚度的变化。假设2b：与立即修复情况相比，在6周进行修复的膝盖中，将存在更大程度的软骨和半月板损害。对于这两种目标，我们都将利用我们特征良好的ACL损伤和修复的青少年迷你猪模型。主要结局指标将包括生物力学（AP膝盖松弛，韧带结构特性）和组织学（细胞密度和血管密度）。次要结局措施包括软骨损伤（印度墨水染色和半月板和关节软骨的组织学）以及修复的材料特性。该提案中的研究旨在确定如果可以使用我们的小说“增强的ACL修复”策略，可以使这些人群中的修复组织更加与未成熟的动物中的修复组织更接近，那么在青少年和成年人中是否可以改善ACL愈合受损。在这项工作中的成功可以改善每年有数十万个青少年和成年患者的ACL眼泪。 公共卫生相关性：美国估计每年有30万至500,000名患者维持前交叉韧带的撕裂（ACL）。即使目前对这种损伤进行了手术治疗，这些患者的过早骨关节炎的风险在损伤中仅14年就接近80％。对于成千上万的青少年，这种伤害会影响，这是一个令人不安的统计数据。我们的工作重点是改善这些伤害的维修。在上一个赠款时期，我们发现年轻动物比青少年或成年动物更好地治愈韧带损伤。在下一项研究中，我们建议确定，如果可以使这些人群中的修复组织更加紧密地与未成熟动物的修复组织相似，那么如果维修补充了为ACL撕裂提供适当的生长因子，则可以使青少年和成年人中注意到的ACL愈合受损。在这项工作中的成功可以改善每年有数十万个青少年和成年患者的ACL眼泪。