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: 9274917
• 负责人: LISA M LARKIN
• 金额: $ 47.36万
• 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/9274917
• 关键词: Acute; Address; Adult; Animals; Area; Behavior; Biology; Blood Vessels; Blood capillaries; Brain; Burn injury; Caliber; Categories; Cells; Clinical; Complex; Development; Disease; Engineering; Engraftment; Environment; Exhibits; Extracellular Matrix; Face; Facial Muscles; Female; Generations; Goals; Hand; Human; Immunologic Markers; Implant; Injury; Kidney; Laboratories; Lead; Ligaments; Liver; Lung; Malignant Neoplasms; Mammals; 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; Pathologic; Patients; Phenotype; Postoperative Period; Production; 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; mechanical load; migration; muscle engineering; muscle pharmacology; muscle regeneration; muscular structure; musculoskeletal injury; nerve supply; new technology; peroneal nerve; precursor cell; public health relevance; 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（由申请人提供）：包括肌肉创伤、手术损伤和肌病在内的多种病理状况可能导致体积性肌肉损失（VML），从而导致肌肉功能无法恢复。迄今为止，包括肌瓣或移植在内的 VML 治疗并不总是有效，并且受到有限的组织可用性和供体部位发病率的阻碍。具有功能性肌腱连接、腱骨锚定和神经支配的工程化肌肉组织的创建不仅可以恢复复杂组织的功能，例如肌肉组织。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肌肉生物学和肌肉药理学的模型。为了满足骨骼肌替代组织的需求，我们的实验室开发了一种具有适当大小和功能的组织工程功能性骨骼肌单元 (SMU)，可用于临床上小型 VML 损伤的情况，例如手和面部的损伤 [1-8]。我们的 SMU 是一种多相复合组织，由工程肌肉组织和工程肌腱和/或骨肌腱锚定端组成。在体内暴露于 VML 环境 28 天后，我们的构建体表现出 SMU 表型的显着改变，包括包裹在广泛的细胞外基质中的单轴排列的肌纤维、骨附着处的完全骨愈合、附着点和肌腱界面的形成、广泛的血管化和神经支配，同时形成神经肌肉接头 (8)。这项令人兴奋的技术实际上会在修复区域添加新的肌肉纤维。我们的研究结果表明，我们的多相复合组织在植入后仍能存活，在体内承受机械负载后仍能存活，并形成将表型推进成人肌肉结构和功能所需的必要界面。虽然我们的技术在修复受损肌肉方面显示出巨大的前景，但仍有大量工作需要确定如何最好地利用该技术来实现损伤部位肌肉功能的最佳恢复。例如，我们需要更完全地恢复原生肌肉力量。关于在人类中使用这种新颖和创新技术的另一个问题是在患者中使用干细胞/前体细胞衍生组织的安全性。至关重要的是，用于生成这些组织构建体的原代细胞或基质细胞在植入后不会造成急性或长期威胁。该领域主要关注的是能否确定移植结构中是否存在未分化细胞，这些细胞随后可能导致异常细胞行为，例如癌症。因此，为了将该技术推向临床应用，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使用 VML 作为模型，从机制上研究我们的 SMU 组织在植入适当的感应组织环境后的整合和再生。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，并对肌肉骨骼组织损伤的治疗具有直接的临床意义。