Acellular composite hydrogel scaffolds for volumetric muscle regeneration

用于体积肌肉再生的脱细胞复合水凝胶支架

• 批准号: 10555267
• 负责人: Jonathan M. Grasman
• 金额: $ 19.92万
• 依托单位: NEW JERSEY INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555267
• 关键词: Ablation; Address; Anastomosis - action; Animal Model; Animals; Architecture; Autologous Transplantation; Benchmarking; Biocompatible Materials; Biological Assay; Biomimetics; Biopolymers; Blood Vessels; Cells; Cellular Infiltrate; Cellular Infiltration; Cicatrix; Circular Dichroism Spectroscopy; Clinical; Collagen; Complement; Cosmetics; Defect; Development; Electron Microscopy; Endothelial Cells; Excision; Future; Generations; Goals; Growth; Health; Histologic; Histology; Human; Hydrogels; Implant; In Situ; In Vitro; Infiltration; Inflammation; Injury; Investigation; Isometric Exercise; Longitudinal Studies; Macrophage; Malignant Neoplasms; Measures; Mechanics; Mediating; Microfabrication; Mus; Muscle; Muscle Contraction; Muscle function; Myogenin; Myosin ATPase; Natural regeneration; Outcome; Output; PECAM1 gene; Patients; Peptides; Phenotype; Porifera; Porosity; Procedures; Production; Quality of life; Rationalization; Recovery of Function; Recruitment Activity; Residual state; Signal Transduction; Site; Skeletal Muscle; Structure; Techniques; Testing; Tissue Engineering; Tissues; Traumatic injury; VWF gene; Vascular Endothelial Growth Factors; Vascularization; Vehicle crash; Weight-Bearing state; Work; angiogenesis; combat injury; design; functional outcomes; graft function; hydrogel scaffold; in vivo; infrared spectroscopy; injured; innovation; mimicry; mouse model; muscle regeneration; nanofiber; neovascularization; nerve supply; nestin protein; permissiveness; preclinical study; recruit; repaired; restoration; satellite cell; scaffold; self assembly; success; tibialis anterior muscle; tissue regeneration; tissue repair; traumatic event; vascular contributions; volumetric muscle loss; wound

Project Summary There are almost 5 million reconstructive procedures performed annually as a result of traumatic injury, cancer ablation, cosmetic procedures, or combat injuries. The destruction or removal of large amounts of skeletal muscle, termed volumetric muscle loss (VML), resulting from traumatic events such as car crashes or combat injuries, represents a significant health concern. Skeletal muscle is highly vascularized, and relies on adequate infiltration of blood vessels to repair and regenerate. The gold standard for VML repair is autologous grafting, and is limited by reduced functional outcomes and inadequate host-mediated graft revascularization. Current biomaterial-based tissue engineered approaches towards the repair of skeletal muscle tissue after VML rely on passive neovascularization from the host, as opposed to actively recruiting vascular networks to accompany satellite cell infiltration during repair. As such, there remains a significant need to develop materials that will actively stimulate the development of vasculature that will guide organized and aligned skeletal muscle tissue regeneration. We hypothesize that scaffolds that stimulate the rapid creation of a new vasculature and aligned muscle tissue will significantly enhance skeletal muscle repair in VML injuries. To test this hypothesis, we will create a class of biodegradable composite scaffolds that will be implanted into VML injuries to enable the recruitment of endothelial cells and satellite cells. As such, the objective is to create a composite material that promotes in situ regeneration of mature functional muscle tissue. To fabricate these scaffolds, collagen sponges with defined, anisotropic architectures will be fabricated and embedded with angiogenic self-assembling peptide hydrogels, termed SLan (Aim 1). Assessment of the mechanics of scaffolds will complement in vitro analyses of cellular infiltration and compatibility to define material parameters that will induce aligned vascularized skeletal muscle tissue. Scaffolds comprised of collagen, SLan, or composites will then be implanted into a murine model of VML to assess the contribution of each material to enhance VML repair (Aim 2). Particular emphasis will be placed on the ability of these scaffolds to support functional recovery as measured by muscular contraction in longitudinal studies. Histologic assessments will characterize i) the cellular infiltrate and the contribution of aligned scaffolds to guide organized skeletal muscle tissue growth, ii) the modulation of in situ neovascularization and supporting structures, and iii) changes in inflammation. Ultimately, we aim to address two major limitations within skeletal muscle tissue regeneration: i) inadequate vascularization of constructs in situ, and ii) the lack of organized alignment of nascent myofibers during repair of VML injuries; both factors known to inhibit functional recovery. These outcomes will result in the creation of a new class of composite materials to functionally drive cellular infiltration with hydrogels that are specifically designed to recruit specific supporting structures necessary for tissue regeneration and repair.

项目概要 每年有近 500 万例因创伤、癌症而进行的重建手术 消融、整容手术或战斗受伤。破坏或移除大量骨骼 肌肉，称为体积肌肉损失（VML），由车祸或战斗等创伤事件引起 伤害，代表着重大的健康问题。骨骼肌是高度血管化的，并且依赖于足够的 渗透血管以修复和再生。 VML修复的金标准是自体移植， 并且受到功能结果降低和宿主介导的移植物血运重建不足的限制。当前的 基于生物材料的组织工程方法修复 VML 后的骨骼肌组织依赖于 来自宿主的被动新生血管形成，而不是主动招募血管网络来伴随 修复过程中卫星细胞浸润。因此，仍然迫切需要开发能够 积极刺激脉管系统的发育，引导骨骼肌组织的组织和排列 再生。我们假设支架可以刺激新血管系统的快速创建并对齐 肌肉组织将显着增强 VML 损伤中的骨骼肌修复。为了检验这个假设，我们将 创建一类可生物降解的复合支架，将其植入 VML 损伤中，以实现 内皮细胞和卫星细胞的募集。因此，我们的目标是创造一种复合材料 促进成熟功能性肌肉组织的原位再生。为了制造这些支架，胶原蛋白海绵 将制造具有明确的各向异性结构并嵌入血管生成自组装肽 水凝胶，称为 SLan（目标 1）。支架力学评估将补充体外分析 细胞渗透和相容性来定义材料参数，从而诱导血管化骨骼对齐 肌肉组织。由胶原蛋白、SLan 或复合材料组成的支架将被植入小鼠模型中 VML 来评估每种材料对增强 VML 修复的贡献（目标 2）。将特别强调的是 放置在这些支架支持功能恢复的能力上，通过肌肉收缩来测量 纵向研究。组织学评估将表征 i) 细胞浸润和贡献 对齐支架以引导有组织的骨骼肌组织生长，ii）原位新血管形成的调节 和支撑结构，以及 iii) 炎症的变化。最终，我们的目标是解决两个主要限制 在骨骼肌组织再生中：i）原位构建体的血管化不足，ii）缺乏 VML 损伤修复过程中新生肌纤维的组织排列；已知这两个因素都会抑制功能 恢复。这些成果将导致创建一类新型复合材料，以实现功能驱动 细胞渗透水凝胶，专门设计用于招募必要的特定支撑结构 用于组织再生和修复。