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: 10372733
• 负责人: Jonathan M. Grasman
• 金额: $ 16.57万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372733
• 关键词: Ablation; Address; Anastomosis - action; Animal Model; Animals; Architecture; Autologous Transplantation; Benchmarking; Biocompatible Materials; Biological Assay; Biomimetics; Biopolymers; Blood Vessels; Cells; Cellular Infiltration; Cicatrix; Circular Dichroism Spectroscopy; Clinical; Collagen; Complement; Cosmetics; Defect; Development; Electron Microscopy; Endothelial Cells; Excision; Future; Generations; Goals; Gold; Growth; Health; Histologic; Histology; Human; Hydrogels; Implant; In Situ; In Vitro; Infiltration; Inflammation; Injury; Investigation; Isometric Exercise; Lead; Leucocytic infiltrate; Longitudinal Studies; 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; Procedures; Production; Quality of life; 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; Vascular regeneration; Vascularization; Vehicle crash; Weight-Bearing state; Work; angiogenesis; base; combat injury; design; functional outcomes; graft function; hydrogel scaffold; in vivo; infrared spectroscopy; injured; innovation; macrophage; mimicry; mouse model; muscle regeneration; nanofiber; neovascularization; nerve supply; nestin protein; preclinical study; reconstruction; recruit; repaired; restoration; satellite cell; scaffold; self assembly; success; tibialis anterior muscle; tissue regeneration; tissue repair; traumatic event; vascular contributions; volumetric muscle loss; wound; Ablation; Address; Anastomosis - action; Animal Model; Animals; Architecture; Autologous Transplantation; Benchmarking; Biocompatible Materials; Biological Assay; Biomimetics; Biopolymers; Blood Vessels; Cells; Cellular Infiltration; Cicatrix; Circular Dichroism Spectroscopy; Clinical; Collagen; Complement; Cosmetics; Defect; Development; Electron Microscopy; Endothelial Cells; Excision; Future; Generations; Goals; Gold; Growth; Health; Histologic; Histology; Human; Hydrogels; Implant; In Situ; In Vitro; Infiltration; Inflammation; Injury; Investigation; Isometric Exercise; Lead; Leucocytic infiltrate; Longitudinal Studies; 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; Procedures; Production; Quality of life; 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; Vascular regeneration; Vascularization; Vehicle crash; Weight-Bearing state; Work; angiogenesis; base; combat injury; design; functional outcomes; graft function; hydrogel scaffold; in vivo; infrared spectroscopy; injured; innovation; macrophage; mimicry; mouse model; muscle regeneration; nanofiber; neovascularization; nerve supply; nestin protein; preclinical study; reconstruction; 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.

项目摘要 由于创伤性损伤，癌症，每年进行了近500万个重建程序 消融，化妆程序或战斗伤害。大量骨骼的破坏或去除 肌肉，称为体积肌肉损失（VML），是由诸如车祸或战斗之类的创伤事件引起的 伤害是一个重大的健康问题。骨骼肌是高度血管化的，并且依赖于足够的 血管修复和再生的血管浸润。 VML维修的金标准是自体嫁接， 并受到功能结果降低和宿主介导的移植血运重建的限制。当前的 VML后，基于生物材料的组织工程方法用于修复骨骼肌组织 从宿主的被动新血管形成，而不是积极招募血管网络 修复过程中的卫星细胞浸润。因此，仍然需要开发材料 积极刺激脉管系统的发展，该脉管系统将引导有组织和对齐的骨骼肌组织 再生。我们假设脚手架会刺激新的脉管系统快速产生并对齐 肌肉组织将显着增强VML损伤中的骨骼肌修复。为了检验这一假设，我们将 创建一类可生物降解的复合支架，将植入VML伤害以实现 募集内皮细胞和卫星细胞。因此，目的是创建一种复合材料 促进成熟功能性肌肉组织的原位再生。为了制造这些脚手架，胶原蛋白海绵 通过定义，各向异性体系结构将被制造并嵌入血管生成的自组成肽 水凝胶，称为Slan（AIM 1）。评估脚手架的力学将补充体外分析 细胞浸润和兼容性定义将诱导比对血管骨骼的材料参数 肌肉组织。然后，由胶原蛋白，Slan或复合材料组成的脚手架将植入鼠模型 VML评估每种材料对增强VML修复的贡献的贡献（AIM 2）。特别强调将是 根据这些支架支持功能恢复的能力，如肌肉收缩在 纵向研究。组织学评估将表征i）细胞浸润和贡献 对准支架以指导有组织的骨骼肌组织生长，ii）原位新生血管的调节 和辅助结构，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）原位构造的血管化不足，ii）缺乏 维修VML损伤时，有组织的新生肌纤维对齐；已知抑制功能的两个因素 恢复。这些结果将导致创建新的复合材料以在功能上驱动 细胞用水凝胶浸润，这些水凝胶是专门设计用于募集特定支撑结构的必要结构的 用于组织再生和修复。