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: 10835331
• 负责人: Jonathan M. Grasman
• 金额: $ 10.22万
• 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/10835331
• 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.

项目摘要 每年有近500万例因创伤性损伤、癌症 消融术、美容手术或战斗损伤。破坏或移除大量的骨骼 肌肉，称为体积肌肉损失（VML），由创伤性事件，如车祸或战斗 伤害，代表了一个重大的健康问题。骨骼肌是高度血管化的，并依赖于足够的 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管再生不足的限制。电流 VML后骨骼肌组织修复的基于生物材料的组织工程方法依赖于 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 修复过程中有卫星细胞浸润因此，仍然非常需要开发将 积极刺激血管系统的发展，这将引导组织和排列的骨骼肌组织 再生我们假设，刺激新血管快速生成并与血管对齐的支架， 肌肉组织将显著增强VML损伤中的骨骼肌修复。为了验证这个假设，我们将 创建一类可生物降解的复合支架，将植入VML损伤， 内皮细胞和卫星细胞的募集。因此，目的是产生一种复合材料， 促进成熟功能性肌肉组织的原位再生。为了制造这些支架，胶原海绵 将制造具有确定的各向异性结构并嵌入血管生成自组装肽 水凝胶，称为SLan（Aim 1）。支架力学的评估将补充体外分析， 细胞浸润和相容性，以确定将诱导对齐的血管化骨骼的材料参数 肌肉组织然后将由胶原蛋白、SLan或复合材料组成的支架植入小鼠模型中 以评估每种材料对增强VML修复的贡献（目标2）。将特别强调 放置在这些支架支持功能恢复的能力，如通过肌肉收缩测量的， 纵向研究。组织学评估将表征i）细胞浸润和以下因素的贡献： 对齐的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 和支持结构，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）原位构建物的血管化不足，和ii）缺乏 VML损伤修复过程中新生肌纤维的有序排列;已知这两种因素抑制功能性 复苏这些成果将导致创造一种新的复合材料， 细胞渗透与水凝胶，专门设计，以招募特定的支持结构， 用于组织再生和修复。