Roles of vascularization and innervation in regenerative medicine

血管形成和神经支配在再生医学中的作用 骨骼肌缺陷，例如由严重车祸等创伤性损伤引起的缺陷， 癌症切除，或战场伤害，代表着一个重大的医疗问题。这些大规模的伤害 压倒骨骼肌中存在的先天修复机制，并导致临床病理称为 容积肌肉损失(VML)。目前对VML修复的护理标准是自体移植，它具有 功能结果降低，并受到重新神经支配和重新血管形成的限制，这最终可能导致 通过组织坏死导致移植物衰竭。有几种组织工程策略被设计用来治疗VML 缺陷；然而，这些策略都不能同时针对血管形成和神经支配。 组织再生包括一系列复杂的协调事件，涉及生长、再血管化、 以及新组织的重新神经支配。通常，组织工程构建的成功受到其能力的限制 与宿主血管和神经组织结合。这些系统通信以支持的程度 人们对再生仍然知之甚少。我们假设血管化和神经支配是至关重要的 在组织再生中指导和维持细胞迁移和分化所需的过程。 此外，我们假设血管形成和神经支配之间的信号是互补的 指示再生。我们将调查这些信号机制的时间性质，以确定 通过设计一种生物材料，在哺乳动物再生中血管先于神经支配，反之亦然。 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元网络的形成(目标1)。同时，我们将 通过以下方法评估仿生结构中的可溶性因子模拟血管形成和神经支配的能力 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，为了解决颅面部VML损伤的临床需要，我们将开发一种带血管和神经的 骨骼肌模型以了解这些过程如何影响和指导骨骼肌组织的形成 通过测量组织构造物的力产生(目标3)。这项提议的总体目标是产生一个 体外培养系统，以了解血管形成和神经支配过程之间的相互作用 阐明相关的信号机制，并最终确定促进组织再生的策略。

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.