Roles of vascularization and innervation in regenerative medicine

血管化和神经支配在再生医学中的作用

• 批准号: 9190519
• 负责人: Jonathan M. Grasman
• 金额: $ 5.77万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-02 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190519
• 关键词: Accidents; Address; Affect; Autologous; Biochemical; Biocompatible Materials; Biological Assay; Biological Models; Biomimetic Materials; Biomimetics; Blood Vessels; Calcium ion; Cell Differentiation process; Cells; Cellular Structures; Chemicals; Clinical; Clinical Pathology; Coculture Techniques; Complex; Cues; Defect; Development; Endothelial Cells; Environment; Enzyme-Linked Immunosorbent Assay; Event; Excision; Extracellular Matrix; Fibronectins; GDNF gene; Goals; Growth; Head; Healthcare; Image; In Vitro; Injury; Lead; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mechanics; Modeling; Morphology; Muscle; Muscular Atrophy; Myoblasts; Myogenin; Myosin ATPase; Natural regeneration; Nature; Neck; Necrosis; Neuromuscular Junction; Neurons; Outcome; Perfusion; Peripheral Nerves; Process; Production; Proteins; Recovery of Function; Regenerative Medicine; Role; Scaffolding Protein; Schwann Cells; Signal Transduction; Silk; Skeletal Muscle; Smooth Muscle Myocytes; Stimulus; Structure; Supporting Cell; System; Techniques; Tissue Engineering; Tissue Model; Tissues; Trauma; Traumatic injury; Tube; Vascular Endothelial Growth Factors; Vascularization; Vehicle crash; alpha Bungarotoxin; axon growth; base; beta Tubulin; cadherin 5; cell motility; cell type; craniofacial; design; functional outcomes; graft failure; in vitro Model; maxillofacial; nerve supply; neuronal growth; repaired; scaffold; standard of care; success; tissue regeneration

ROLES OF VASCULARIZATION AND INNERVATION IN REGENERATIVE MEDICINE Skeletal muscle defects, such as those presented from traumatic injuries such as severe car crashes, cancer resections, or battlefield injuries, represent a significant healthcare problem. These large scale injuries overwhelm the innate repair mechanisms present in skeletal muscle and result in the clinical pathology termed volumetric muscle loss (VML). The current standard of care for VML repair is an autologous graft, which has a reduced functional outcome and is limited by re-innervation and re-vascularization, which may ultimately result in graft failure via tissue necrosis. There are several tissue engineered strategies designed to treat VML defects; however, none of these strategies simultaneously target vascularization and innervation. Tissue regeneration includes a complex set of coordinated events involving the growth, re-vascularization, and re-innervation of new tissue. Often, the success of tissue engineered constructs is limited by their ability to integrate with host vascular and neuronal tissue. The extent to which these systems communicate to support regeneration remains poorly understood. We hypothesize that vascularization and innervation are critical processes that are required to direct and sustain cell migration and differentiation in tissue regeneration. Further, we hypothesize that the signaling between vascularization and innervation are complementary to instruct regeneration. We will investigate the temporal nature of these signaling mechanisms to determine if vascularization precedes innervation, or vice versa, in mammalian regeneration by designing a biomaterial system where the distance between the two cell types and the availability of extracellular matrix molecules will be systematically varied to assess vascular and neuronal network formation (Aim 1). Concurrently, we will assess the ability of soluble factors within biomimetic constructs to model vascularization and innervation by determining the maturity and functionality of these tissue structures in a controlled in vitro environment (Aim 2). Finally, to address the clinical need of craniofacial VML injuries, we will develop a vascularized and innervated skeletal muscle model to understand how these processes affect and instruct skeletal muscle tissue formation by measuring force production of tissue constructs (Aim 3). The overall goal of this proposal is to generate an in vitro culture system to understand the interactions between vascularization and innervation processes, to elucidate signaling mechanisms involved, and ultimately to identify strategies to enhance tissue regeneration.

血管化和神经支配在再生医学中的作用 骨骼肌缺陷，例如因严重车祸等外伤而出现的缺陷， 癌症切除或战场伤害是一个重大的医疗保健问题。这些大规模的伤害 压倒骨骼肌中存在的先天修复机制，导致临床病理学称为 体积肌肉损失（VML）。目前 VML 修复的护理标准是自体移植，其具有 功能结果降低，并受到重新神经支配和重新血管化的限制，这最终可能导致 由于组织坏死导致移植失败。有多种组织工程策略可用于治疗 VML 缺陷；然而，这些策略都没有同时针对血管化和神经支配。 组织再生包括一系列复杂的协调事件，涉及生长、血管重建、 和新组织的重新神经支配。通常，组织工程构建体的成功受到其以下能力的限制： 与宿主血管和神经组织整合。这些系统通信支持的程度 再生仍然知之甚少。我们假设血管化和神经支配至关重要 组织再生中指导和维持细胞迁移和分化所需的过程。 此外，我们假设血管化和神经支配之间的信号传导是互补的 指导再生。我们将研究这些信号机制的时间性质，以确定是否 通过设计生物材料，在哺乳动物再生中，血管化先于神经支配，反之亦然 系统中两种细胞类型之间的距离和细胞外基质分子的可用性将 系统地改变以评估血管和神经网络的形成（目标 1）。同时，我们将 评估仿生结构中可溶性因子模拟血管化和神经支配的能力 在受控的体外环境中确定这些组织结构的成熟度和功能（目标 2）。 最后，为了满足颅面VML损伤的临床需求，我们将开发一种血管化和神经支配的 骨骼肌模型来了解这些过程如何影响和指导骨骼肌组织的形成 通过测量组织结构的力产生（目标 3）。该提案的总体目标是产生一个 体外培养系统，以了解血管化和神经支配过程之间的相互作用， 阐明所涉及的信号传导机制，并最终确定增强组织再生的策略。