Utilization of Engineered Skeletal Muscle Units to Repair Volumetric Muscle

利用工程骨骼肌单位修复体积肌

• 批准号: 9198665
• 负责人: LISA M LARKIN
• 金额: $ 6.93万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198665
• 关键词: Acute; Address; Adult; Animals; Area; Behavior; Biology; Blood Vessels; Blood capillaries; Brain; Burn injury; Caliber; Categories; Cells; Clinical; Complex; Cytoskeleton; Development; Disease; Engineering; Engraftment; Environment; Exhibits; Face; Facial Muscles; Female; Generations; Goals; Hand; Health; Human; Immunologic Markers; Implant; Injury; Kidney; Laboratories; Lead; Ligaments; Liver; Lung; Malignant Neoplasms; Mammals; Mechanics; Methodology; Modeling; Monitor; Morbidity - disease rate; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Muscular Atrophy; Musculoskeletal; Myopathy; Natural regeneration; Nerve; Neuromuscular Junction; Operative Surgical Procedures; Patients; Phenotype; Postoperative Period; Production; Proliferation Marker; Recovery; Regenerative Medicine; Regenerative response; Safety; Sheep; Signal Transduction; Site; Skeletal Muscle; Stem cells; Stromal Cells; Study models; Surgical Flaps; System; Technology; Tendon structure; Testing; Time; Tissue Engineering; Tissue Grafts; Tissues; Transplantation; Trauma; Traumatic injury; Undifferentiated; Vascularization; Work; bone; bone healing; capillary; cell type; clinical application; clinically relevant; functional restoration; implantation; in vivo; in vivo regeneration; injured; innovative technologies; insight; interest; male; migration; muscle pharmacology; muscle regeneration; muscular structure; musculoskeletal injury; nerve supply; new technology; peroneal nerve; precursor cell; regenerative therapy; repaired; response; satellite cell; scale up; skeletal muscle wasting; spatial relationship; stem; stem cell biology; tissue regeneration

 DESCRIPTION (provided by applicant): Multiple pathological conditions including muscle trauma, surgical damage, and myopathies can lead to volumetric muscle loss (VML) resulting in unrecoverable muscle function. To date, the treatments for VML including the muscle flap or graft are not always effective and are hindered by limited tissue availability and donor site morbidity. The creation of engineered muscle tissue with functional myotendinous junctions, tendon- bone anchors and innervation will not only restore the function of a complex tissue, e.g. a small facial muscle following traumatic injury or disease, but can also be used as a model for studying developmental muscle biology and muscle pharmacology. To address the need for skeletal muscle replacement tissue, our laboratory has developed a tissue-engineered functional skeletal muscle unit (SMU) of appropriate size and function for clinical use in situations of small VML injuries, such as those found in the hand and face [1-8]. Our SMU is a multi-phasic composite tissue consisting of engineered muscle tissue with engineered tendon and/or bone- tendon anchor ends. After twenty-eight days of exposure in vivo to a VML environment, our constructs exhibited significant alteration to the SMU phenotype including uniaxial aligned muscle fibers encased in an extensive extra-cellular matrix, complete bone healing at the bone attachment, formation of enthesis and myotendinous interfaces , extensive vascularization and innervation with concomitant formation of neuromuscular junctions (8). This exciting technology actually results in the addition of new muscle fibers to the repair area. Our findings show that our multi-phasic composite tissue survives implantation, survives the mechanical loads placed on them in vivo, and develops the necessary interfaces needed to advance the phenotype toward adult muscle structure and function. While our technology shows great promise for the repair of damaged muscle, a lot of work remains to determine how best to utilize this technology to obtain optimal recovery of muscle function to an injury site. For example, we need more complete recovery of native muscle forces. An additional concern regarding the use of this novel and innovative technology in humans is the safety of use of stem/precursor cell-derived tissue in patients. It is imperative that the primary or stromal cells used for the generation of these tissue constructs pose no acute or long-term threat after implantation. The main concern in the field is the ability to ascertain that no undifferentiated cels persist in the transplanted construct that might later lead to aberrant cellular behavior such as cancer. Thus, to progress this technology towards clinical application, the mechanisms of graft tissue integration, regeneration, and repair must be elucidated. The overall goal of this proposal is to use VML as a model for looking mechanistically at the integration and regeneration of our SMU tissue following implantation into an appropriate inductive tissue environment. This work has broad implications for stem cell biology, musculoskeletal biology and regenerative medicine as well as direct clinical relevance for the treatment of musculoskeletal tissue injuries.

 描述（由适用提供）：多种病理状况，包括肌肉创伤，手术损伤和肌病可能导致体积肌肉损失（VML），从而导致无法恢复的肌肉功能。迄今为止，包括肌肉皮瓣或谷物在内的VML处理的处理并不总是有效的，并且受到组织可用性有限和供体部位的发病率的阻碍。创建具有功能性肌腱连接的工程肌肉组织，肌腱锚和神经不仅会恢复复杂组织的功能，例如创伤性损伤或疾病后的小面部肌肉，但也可以用作研究发育生物学和肌肉药理学的模型。为了满足对骨骼肌置换组织的需求，我们的实验室已经开发了组织工程设计的功能性骨骼肌单位（SMU），具有适当的大小和功能，可在小VML损伤的情况下进行临床使用，例如在手和脸上发现的情况[1-8]。我们的SMU是一种由工程肌肉组织和工程肌腱和/或骨腱锚末端组成的多重复合组织。在体内暴露于VML环境中的二十八天之后，我们的结构对SMU表型暴露了重大变化，包括包裹在广泛的细胞外基质中的单一对齐的肌肉纤维，在骨外的骨外完全愈合，在骨骼附着，触点形成和肌齿状互动，广泛的血管化和连续性（8型）的形成（骨膜化）（8）。这种令人兴奋的技术实际上导致在维修区域中添加了新的肌肉纤维。我们的发现表明，我们的多重复合组织可以在体内生存，生存在体内的机械载荷，并开发出将表型推向成人肌肉结构和功能所需的必要界面。虽然我们的技术对修复受损的肌肉的维修非常有前途，但仍有许多工作要确定如何最好地利用这项技术来获得最佳的肌肉功能，从而为伤害部位恢复。例如，我们需要对本地肌肉力量进行更多完整的恢复。关于这种新颖和创新技术在人类中使用的另一个问题是，患者使用茎/前体细胞衍生的组织的安全性。必须在植入后不构成急性或长期威胁的主要或基质细胞或基质细胞。该领域的主要关注点是能够确定在移植的构建体中不存在未分化的CEL，这可能会导致癌症等异常的细胞行为。为了使这项技术朝着临床应用发展，必须阐明移植组织整合，再生和修复的机制。该提案的总体目标是将VML用作机械植入适当的电感组织环境后SMU组织的整合和再生的模型。这项工作对干细胞生物学，肌肉骨骼生物学和再生医学具有广泛的影响，以及对治疗肌肉骨骼组织损伤的直接临床意义。