Using BMSC-derived Bone-Ligament-Bone Tissue as a Live Template for ACL Regenerat

使用 BMSC 衍生的骨韧带骨组织作为 ACL 再生的实时模板

• 批准号: 8383131
• 负责人: Deneen M Wellik
• 金额: $ 20.99万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8383131
• 关键词: Acute; Address; Adult; Allogenic; Allografting; Animal Model; Anterior Cruciate Ligament; Autologous Transplantation; Behavior; Biology; Biomechanics; Bone Marrow; Bone Tissue; Cadaver; Caring; Cells; Characteristics; Child; Childhood; Chromosome Painting; Collaborations; Connective Tissue; Data; Degenerative polyarthritis; Development; Embryonic Development; Engineering; Ensure; Exhibits; Female; Generations; Goals; Growth Factor; Healthcare; Human; Implant; Injury; Innovative Therapy; Joints; Knee Injuries; Laboratories; Lead; Life; Ligaments; Malignant Neoplasms; Mammals; Maps; Mesenchymal; Molecular; Musculoskeletal; Natural regeneration; Operative Surgical Procedures; Organ Transplantation; Outcome; Pathway interactions; Patients; Population; Procedures; Process; Quality of life; Replacement Therapy; Research; Risk; Safety; Sheep; Signal Transduction; Stem cells; Stromal Cells; Technology; Tendon structure; Time; Tissue Differentiation; Tissue Engineering; Tissues; Translating; Transplantation; Transplanted tissue; Treatment Efficacy; Undifferentiated; Work; Y Chromosome; anterior cruciate ligament reconstruction; base; bone; bone engineering; cell motility; cost; early onset; hamstring; high risk; implantation; improved; in vivo; in vivo regeneration; injured; innovation; ligament injury; male; molecular marker; musculoskeletal injury; new technology; novel; precursor cell; regenerative; regenerative therapy; repaired; response; scaffold; spatiotemporal; stem; success; young adult

DESCRIPTION (provided by applicant): Approximately 350,000 anterior cruciate ligament (ACL) reconstruction surgeries are performed each year, and billions of dollars are spent on the acute care costs involved in this procedure. The most common ACL replacement strategies involve grafts (allografts from cadavers or autografts of the patients' own patellar or hamstring tendons), although newer, more experimental treatments use engineered tissues that typically involve seeding cells on a polymeric scaffold. In these procedures, the graft or engineered tissue never fully integrates with the bone tunnel created during surgery and the joint never recovers pre-surgical level biomechanics. Not surprisingly, more than half of the patients who have undergone this procedure develop early-onset osteoarthritis (OA). With acute ACL injuries becoming increasingly prevalent in children, the number of young adults developing OA is increasing each year. The Larkin and Arruda laboratories have spent the last several years engineering an ACL replacement construct generated from bone marrow-derived stromal cells (BMSCs) that exhibits the structural and functional interface characteristics of native ACL when transplanted in vivo. The construct is composed of an engineered ligament with engineered bone at each end; it fully integrates into the recipient bone and differentiates in vivo to form a mechanically appropriate and biologically matched interface between the two tissues. Work from these laboratories demonstrates many advantages to this strategy and evidence in a large animal model supports its superiority for replacement therapy. One critical concern regarding the use of this novel and innovative therapy in humans, however, is the safety of use of stem/precursor cell-derived tissue in patients. It is imperative to demonstrate that the BMSCs used for the generation of these constructs pose no long-term threat after transplantation. The main concern in the field is the ability to ascertain that no undifferentiated cells persist in the transplanted construct that might later lead to aberrant cellular behavior such as cancer. In collaboration with Dr. Wellik's laboratory, a recent examination of the fate of the BMSC-derived BLB construct led to the surprising discovery that within several months after implantation of the BLB, donor construct cells are replaced entirely by recipient cells and donor-derived cells are no longer present. Thus, by transplanting a developmentally immature, exogenous live tissue template for replacement, adult recipient cells are induced to fully regenerate a viable and mechanically appropriate replacement ligament! This proposal seeks to confirm these preliminary results and initiate exploration into the mechanisms of this remarkable regenerative process, with the longer-term goal of translating this innovative therapy into humans and vastly improving the outcomes of acute ACL and potentially other joint and connective tissue injuries. PUBLIC HEALTH RELEVANCE: Billions of dollars are spent each year on anterior cruciate ligament (ACL) reconstructions after acute knee injury and more than half of patients who undergo this procedure develop early- onset osteoarthritis. New technology developed by this research team uses bone marrow stromal cell-derived, living bone-ligament-bone templates to replace the injured ACL. Transplanted tissue does not survive long-term in the recipient (patient), but induces the regeneration of a new ligament made entirely of the patient's own cells! The regenerating ACL integrates into bone and forms a viable and mechanically appropriate replacement ligament. If these preliminary results are confirmed, we will be one large step closer to translating these results into a vastly improved human therapy. Further, understanding the mechanisms by which this regeneration occurs will open new avenues in the regeneration of musculoskeletal tissue.

描述（由申请人提供）：每年约有350，000例前交叉韧带（ACL）重建手术，数十亿美元用于该手术所涉及的急性护理费用。最常见的ACL置换策略涉及移植物（来自尸体的同种异体移植物或患者自身髌骨或腘绳肌腱的自体移植物），尽管更新的更具实验性的治疗使用通常涉及在聚合物支架上接种细胞的工程组织。在这些手术中，移植物或工程组织从未与手术期间创建的骨隧道完全整合，并且关节从未恢复手术前水平的生物力学。毫不奇怪，超过一半的接受过这种手术的患者会患上早发性骨关节炎（OA）。随着急性ACL损伤在儿童中越来越普遍，患OA的年轻人数量每年都在增加。Larkin和Arruda实验室在过去的几年里一直在设计一种由骨髓源性基质细胞（BMSC）产生的ACL替代结构，该结构在体内移植时表现出天然ACL的结构和功能界面特征。该结构由两端带有工程化骨的工程化韧带组成;它完全整合到受体骨中，并在体内分化，以在两种组织之间形成机械上适当且生物学上匹配的界面。这些实验室的工作证明了这种策略的许多优点，大型动物模型中的证据支持其替代疗法的优越性。然而，关于在人类中使用这种新型和创新疗法的一个关键问题是在患者中使用干细胞/前体细胞衍生组织的安全性。必须证明用于生成这些构建体的BMSC在移植后不会造成长期威胁。该领域的主要关注点是确定没有未分化细胞存在于细胞中的能力。 移植的构建体，可能会导致异常的细胞行为，如癌症。与Wellik博士的实验室合作，最近对BMSC衍生的BLB构建体的命运的检查导致了令人惊讶的发现，即在BLB植入后的几个月内，供体构建体细胞完全被受体细胞取代，并且供体衍生的细胞不再存在。因此，通过移植发育不成熟的外源性活组织模板用于替代，诱导成年受体细胞完全再生可行的和机械上适当的替代韧带！该提案旨在确认这些初步结果，并开始探索这一非凡再生过程的机制，长期目标是将这种创新疗法转化为人类，并大大改善急性ACL和其他潜在关节和结缔组织损伤的结果。 公共卫生相关性：每年花费数十亿美元用于急性膝关节损伤后的前交叉韧带（ACL）重建，超过一半的接受这种手术的患者患有早发性骨关节炎。该研究小组开发的新技术使用骨髓基质细胞衍生的活骨-韧带-骨模板来替换受伤的ACL。移植的组织不能在接受者（患者）体内长期存活，但可以诱导完全由患者自身细胞组成的新韧带再生！再生的ACL整合到骨中并形成可行的和机械上适当的替代韧带。如果这些初步结果得到证实，我们将更接近于将这些结果转化为一种大大改进的人类疗法。此外，了解这种再生发生的机制将为肌肉骨骼组织的再生开辟新的途径。